Multiple brain pathologies in dementia are common

European Geriatric Medicine 1 (2010) 259–265

Research paper

Multiple brain pathologies in dementia are common M. Woodward a,*, I.R.A. Mackenzie b,1, G.-Y. R. Hsiung c,2, C. Jacova d,3, H. Feldman e,f,4 a

Aged Care Services, Heidelberg Repatriation Hospital, University of Melbourne, Austin Health, PO Box 5444, Heidelberg West VIC 3081 Australia Neuropathology Department of Pathology Vancouver General Hospital, 855 West 12th Avenue, Vancouver, British Columbia Canada V5Z 1M9 c Division of Neurology, Department of Medicine, University of British Columbia, S162-2211 Wesbrook Mall, UBC Hospital, Vancouver, BC, Canada V6T 2B5 d UBC Hospital, 2211 Wesbrook Mall, Vancouver, BC, Canada V6T 2B5 e Dept of Neurology, Yale University, New Haven, CT, USA f Neuroscience Global Clinical Research, Bristol-Myers Squibb, Wallingford, CT, USA b

A R T I C L E I N F O

A B S T R A C T

Article history: Received 22 July 2010 Accepted 28 July 2010 Available online 26 August 2010

Multiple pathological processes are common in those with dementia and can affect clinical presentations. This study defined the extent of multiple pathological processes at autopsy in a well-characterized dementia clinic population and determined their impact on cognitive deficits. Forty-five cases from the Canadian Collaborative Cohort of Related Dementia (ACCORD) were prospectively assigned one primary clinical diagnosis and up to one secondary clinical diagnosis. Neuropathological examination followed a uniform protocol including mandatory semiquantitative assessment of a wide range of pathological changes. Multiple significant pathologies were identified in 21 cases (46.7%) including 19 cases with two cases with three pathological diagnoses. The pathological diagnoses in these mixed cases included Alzheimer disease (AD) (n = 18), dementia with Lewy Bodies (DLB) (n = 9, eight also with AD), frontotemporal lobar degeneration with TDP-43-positive inclusions (FTLD-TDP) (n = 10, eight with coexisting AD), cerebrovascular disease (CVD) (n = 5, three cases with coexisting AD) and progressive supranuclear palsy (PSP) (n = 1, also with CVD and FTLD-TDP). Only two cases with multiple pathological diagnoses were all recognized in the clinical diagnoses. Additional pathology of uncertain significance in 24 cases included vascular lesions, argyrophilic grains and hippocampal sclerosis. Patients with multiple pathologies were older and their baseline MMSE score higher at presentation. ß 2010 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved.

Keywords: Dementia Neuropathology Clinical-pathological correspondence Dementia cohort study

1. Introduction There is increasing recognition that multiple pathological processes are common in those with a clinical diagnosis of dementia [1,2]. It is also recognized that the presence of multiple pathological processes can increase the cognitive deficits of those with dementia in an additional fashion. The presence of cerebral infarction in patients with Alzheimer’s disease (AD) is associated with greater overall severity of clinical dementia and poorer performance on specific cognitive tests [3]. The Nun Study has shown that in 61 participants meeting the neuropathological criteria for AD, those who also had brain

* Corresponding author. Tel.: +613 9496 2185; fax: +613 9296 2613. E-mail addresses: [email protected] (M. Woodward), [email protected] (I.R.A. Mackenzie), [email protected] (G.-Y. R. Hsiung), [email protected] (C. Jacova), [email protected] (H. Feldman). 1 Tel.: +604 875 4480; fax: +604 875 5707. 2 Tel.: +604 822 3610; fax: +604 822 7177. 3 Tel.: +604 822 7540; fax: +604 822 7703. 4 Tel.: +203 677 7183; fax: +203 677 7695.

infarcts had poorer cognitive function and a higher prevalence of dementia than those without infarcts [4]. Additionally, in patients with similar degrees of Alzheimer’s dementia, the presence of cerebrovascular lesions is associated with a lesser degree of AD pathology, suggesting cerebrovascular disease (CVD) contributes to the severity of cognitive impairment in those with AD [5,6]. Whether multiple brain pathologies of other types have clinical significance in patients with dementia is less well known. Lewy bodies (LB) are often found in those fulfilling neuropathological criteria for AD [7,8]. However, the clinical effects of coexistent LB pathology on the severity of AD are not as well characterized as for coexistent vascular pathology. A study which included 48 patients with AD pathology alone, 65 with both LB and AD pathology (mixed AD/LB) and 22 with LB pathology alone found more severe memory impairment in the AD and the mixed AD/LB groups than in those with LB pathology alone [9]. This study also found that those with mixed AD/LB pathology had the greatest rate of cognitive decline. Another study of 34 patients showed that concomitant AD and LB pathology was associated with increased dementia severity when compared with those with LB and no AD pathology [10].

1878-7649/$ – see front matter ß 2010 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved. doi:10.1016/j.eurger.2010.07.012

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M. Woodward et al. / European Geriatric Medicine 1 (2010) 259–265

Several recent studies have described the presence of pathological TDP-43 inclusions, in cases of AD, LB disease and other neurodegenerative conditions [11–15]. These changes are similar to the characteristic pathology found in the most common pathological subtype of frontotemporal lobar degeneration, originally referred to as FTLD with ubiquitinated inclusions (FTLD-U) and now designated FTLD-TDP [16]. Although the role of this coexistent TDP-43 in the disease pathogenesis and its influence on the clinical phenotype is currently not known, one study found that cases of AD with TDP-43 pathology had more severe dementia [17]. Argyrophilic grain disease (AGD) has been shown to lower the threshold for cognitive deficits in those with moderate amounts of AD-related pathology [18] while the effect of hippocampal sclerosis (HS) is not known. Similarly, the effects of the various subtypes of FTLD, and other pathology, when coexistent with AD pathology, is not known. We hypothesized that, in an autopsy series following a systematic neuropathology protocol in a prospectively well-characterized population of people with dementia, multiple neuropathologies relevant to cognitive impairment would be common. Furthermore, we hypothesized that the presence of multiple pathologies would affect the clinical expression of dementia, including a greater severity of initial presentation. 2. Methods The Canadian Collaborative Cohort of Related Dementia (ACCORD) study evaluated the clinical diagnoses, natural history and treatment outcomes of individuals newly referred from the community to eight university-based dementia clinics in Canada [19]. Each site enrolled as many as possible consecutive newly referred patients that fulfilled the inclusion criteria after informed consent. The diagnosis of dementia was made when all the criteria on DSM-IIIR were fulfilled [20]. If the subject was diagnosed with dementia, the investigator would then assign one primary clinical diagnosis, and up to one further secondary clinical diagnosis if needed. The primary diagnosis was assigned as the most significant clinical cause of the subject’s dementia. A secondary diagnosis was assigned when the investigator felt that the disease was contributing significantly to the clinical presentation, but was not the main cause of the cognitive disorder. The clinical diagnosis of AD was based on the NINCDSADRDA criteria [21]. Vascular dementia (VaD) was diagnosed based on the presence of history of stroke, neurological signs consistent with previous cerebrovascular accidents, risk factors, or neuroimaging data consistent with stroke or chronic small vessels ischemic changes. Frontotemporal dementia (FTD) was diagnosed based on criteria published by the Lund and Manchester group [22]. Dementia with Lewy bodies (DLB) was diagnosed by the criteria of McKeith et al. [23]. The final clinical diagnosis was made by the individual clinician in charge, often with input from other team members at a multidisciplinary clinical meeting. Independent panel review of the clinical diagnosis was not utilized. In patients who came to autopsy, neuropathological examination followed a standardized protocol in which semiquantitative assessment of a wide range of pathological changes was mandatory. The ACCORD neuropathology protocol was developed to be as unbiased as possible and not presuppose that one type of pathology would have a greater influence on the clinical presentation than another. Therefore, each type of pathology was graded independently and an assessment was made as to whether or not it was of sufficient severity to have independently caused dementia or contributed to dementia in an additive fashion. The weight of the brain was recorded and there was a gross

examination of the external surface and cut sections. Any focal lesions, the degree of atrophy of normal anatomical structures and the degree and pattern of ventricular enlargement were recorded. Tissue sections for histology were taken from standardized anatomical regions that included the neocortical regions used in the CERAD protocol (superior and medial temporal gyri, middle frontal gyrus, inferior parietal lobule as well as the hippocampus, entorhinal cortex and midbrain) [24]. Additional tissue blocks were taken from regions where gross focal lesions were seen. The specific pathological features assessed and the method of quantitation used was based on published criteria (see below), utilizing the most recent interpretation provided in the literature. Since there is little knowledge of the exact burden of specific pathologies needed to cause dementia, assessment of the significance of each pathology was necessarily subjective. In general, the tendency was to err on the side of not overestimating the impact. A diagnosis of AD was given when numerous or moderate neuritic senile plaques (SP) and numerous or moderate neurofibrillary tangles (NFT) were present in the neocortex, fulfilling the NIA Reagan Criteria for a high or intermediate likelihood of AD [25]. Cases with absent or sparse SP and absent or sparse NFT were not given an AD diagnosis. Cortical LBs were quantified according to the original consensus criteria for DLB [23]. A diagnosis of DLB was given when LB were present in the limbic and/or neocortex. The presence of LBs in the amygdala only was not sufficient to make a diagnosis of DLB. The size, number and anatomical location of all macroscopic and microscopic chronic infarcts and hemorrhages were recorded. Recent vascular disease was not considered relevant to dementia. Large vessel stenosis, arteriolosclerosis, cerebral amyloid angiopathy and white matter rarefaction/demyelination were all graded in a semiquantitative fashion (none, mild, moderate, severe) and taken into account when assessing the overall degree of CVD. The following patterns of CVD were considered to have possibly caused or contributed to dementia:  single large chronic cerebral infarcts;  numerous smaller chronic lesions affecting multiple anatomical regions of both hemispheres;  lesions affecting critical anatomical structures (e.g. bilateral hippocampi);  extensive ischemic injury to subcortical white matter [26] and thus led to a pathological diagnosis of CVD-related dementia. All other vascular pathology was considered incidental to the pathological diagnosis. The diagnosis of FTLD-U was originally based on the presence of neuronal cytoplasmic inclusions and neurites in the neocortex that were immunoreactive for ubiquitin but did not stain for tau or alpha-synuclein [27]. Following the discovery of TDP-43 as the pathological protein in FTLD-U [28], assessment of TDP-43 immunohistochemistry was added to the ACCORD neuropathology protocol. There is currently some controversy as to whether a diagnosis of FTLD-TDP should be made when TDP-43 pathology is found to coexist with another neurodegenerative condition such as AD [16]. In keeping with the unbiased approach used elsewhere in the ACCORD study, we allowed FTLD-TDP as an additional diagnosis when this pathology was found to extend into the cerebral neocortex, thus resembling cases of pure FTLD-TDP. However, no additional diagnosis was made when TDP-43 pathology had a more restricted anatomical distribution. Diagnoses of less common causes of dementia, such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick’s disease (PiD) and AGD were based on recognition of each of their characteristic pathologies [29–33]. Some degree of

M. Woodward et al. / European Geriatric Medicine 1 (2010) 259–265

AGD is known to coexist with a variety of other neurodegenerative conditions [34,35]. AGD was only given as a diagnosis if it was severe, easy to identify and not combined with another pathological process with which it commonly associates. HS was defined as near complete loss of pyramidal neurons from the CA1 sector of hippocampus and the subiculum. HS was only considered to be a pathological diagnosis in the absence of other pathological processes that can cause a similar pattern of neurodegeneration. The current study is based on data from 45 cases that have come to autopsy at a single site (Vancouver).

Table 1 Pathological and clinical diagnoses.

3. Results In 24 cases (53%), a single pathological process was identified as the likely cause of dementia (Table 1). These included AD (n = 19, 42% of total), CVD (n = 2, 4%), PiD (n = 2, 4%) and NFT predominant dementia (n = 1, 2%). Of the 21 cases (47%) with multiple pathological diagnoses, 18 cases (40% of total) had AD combined with one or more other processes (FTLD-TDP alone, n = 7; DLB alone n = 8; CVD alone, n = 2; DLB and CVD, n = 2; FTLD-TDP and CVD, n = 1). The post common pathological diagnosis was AD, either alone or in combination with other pathological diagnoses. In the cases with a single pathology, the primary clinical diagnosis matched the pathological diagnosis in 21 (88%), including 17/19 (90%) cases with pure AD, both cases of PiD (diagnosed as FTD clinically) and both cases with only CVD (including a case of CADASIL). Two cases with pure AD pathology had received a primary clinical diagnosis of FTD, although, in one of these, AD was given as the secondary clinical diagnosis. There was one case with a primary clinical diagnosis of AD and a secondary diagnosis of CVD in which the only significant pathology was NFT and mild AGD restricted to the mesial temporal lobe. There were no SP in this case and a pathological diagnosis of NFT-predominant dementia was made. Therefore, in only two cases (8%) with a single pathology was this diagnosis not considered during life. Of the 21 cases with multiple pathologies (Table 1), only two (10%) had all the pathological diagnoses reflected in the clinical diagnoses (one case of AD/DLB and another of AD/CVD). There were 14 cases in which a single clinical diagnosis was given and confirmed by pathology but the additional pathologies present were not clinically suspected. These included 13 cases diagnosed as pure AD, that had AD pathology combined with one or more of DLB, CVD and/or FTLD-TDP. There was also one case in which FTD was the only clinical diagnosis that had AD pathology in addition to FTLD-TDP. In two other cases, the primary clinical diagnosis of AD was confirmed pathologically but the secondary clinical diagnosis of VaD did not match the pathological findings (one had DLB and one FTLD-TDP). One case with a primary clinical diagnosis of AD and secondary clinical diagnosis of VaD was found to have DLB and CVD pathology. Finally, there were two cases where none of the pathological diagnoses was reflected in the clinical diagnoses. One with clinical diagnoses of AD and alcohol-related dementia was found to have PSP, FTLD-TDP and CVD pathology. Another case

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Pathological diagnosis

N

Single pathology AD

24 19

CVD

2

PiD NFT dementia

2 1

Multiple pathologies AD + DLB

21 8

AD + FTLD-U

7

AD + CVD

2

AD + FTLD-U + CVD DLB + CVD PSP + CVD + FTLD-U FTLD-U + AGD

1 1 1 1

Clinical diagnosis (primary/secondary)

N

AD AD/VaD AD/FTD AD/trauma FTD FTD/AD VaD VaD/AD FTD AD/VaD

14 1 1 1 1 1 1 1 2 1

6 1 1 5 1 1 1 1 1 1 1 1

AD DLB/AD AD/VaD AD AD/VaD FTD AD/VaD AD AD AD/VaD AD/Alc AD

AD: Alzheimer’s dementia; CVD: cerebrovascular disease related dementia; FTD: (clinical) frontotemporal dementia; VaD: vascular dementia; PiD: Pick’s disease; NFT: neurofibrillary tangle; FTLD-U: frontotemporal lobar degeneration with ubiquitin-immunoreactive inclusions; DLB: dementia with Lewy bodies; Alc: alcohol-related dementia; AGD: agyrophilic grain disease. Bold: cases where all clinical diagnoses matched all pathological diagnoses.

with a pure AD clinical diagnosis had FTLD-TDP and AGD pathology. Of those with multiple pathologies, 19 subjects (90%) had a total of 22 pathological processes that were not reflected in the clinical diagnoses. The seven cases with sufficient cerebrovascular pathology to diagnose CVD as a pathological cause of the dementia, either alone or in combination with another pathological diagnosis, are further detailed in Table 2. All had macroinfarction and most also had evidence of microinfarction. No hemorrhages were found. A number of other pathological changes were identified but felt unlikely to have independently contributed to dementia. There were 33 findings in 24 cases (53.3% of the total cases). Twelve of these cases had AD as the only pathological diagnosis. In 10 cases with AD as the primary pathological diagnosis, with or without additional pathological diagnoses, there were additional nondiagnostic neuropathological findings. Incidental CVD pathology was found in nine cases without a pathological diagnosis of CVDrelated dementia. A total of 29 cases had some cerebrovascular pathology, whether felt sufficient to contribute to a pathological diagnosis or not. Seven cases had HS but all of these were in the setting of coexisting FTLD-TDP and therefore HS was not considered to be a separate pathological diagnosis. A mild degree of AGD was present

Table 2 Pathological findings in cases with pathological diagnoses of cerebrovascular dementia. Pathology

Case no. 1

Case no. 2

Case no. 3

Case no. 4

Case no. 5

Case no. 6

Case no. 7

Large vessel stenosis Macroinfarction Microinfarction White matter lesions Congophilic amyloid angiopathy Hemorrhage Pathological diagnosis/es

N Y Y 2 0 0 CVD

N Y N 1 0 0 DLB/CVD

N Y N 1 0 0 PSP CVD FTLD-U

N Y Y 2 2 0 AD CVD

N Y Y 2 0 0 CADASIL

N Y Y 1 1 0 AD CVD

N Y Y 1 0 0 AD FTLD-U CVD

Y: yes; N: no; 0: absent; 1: mild; 2: moderate; 3: severe.

M. Woodward et al. / European Geriatric Medicine 1 (2010) 259–265

262 Table 3 Clinical features at initial assessment. Feature

Only one pathological diagnosisa

More than one pathological diagnosisa

P value for differences between groups

Test used

Gender: % Male Age at diagnosis (Yr) Age at assessment (Yr) Education (Yr) MMSE 3MS DAD FRS NPI CIRS

44.4 69.9 (10.5) 74.4 (10.38) 12.7 (3.81) 20.4 (6.01) 64.8 (20.2) 65.3 (20.6) 23.0 (5.30) 16.1 (16.4) 5.5 (4.18)

55.6 74.5 (6.7) 79.6 (7.10) 12.0 (3.71) 23.6 (3.85) 73.0 (13.7) 72.2 (17.7) 22.1 (4.07) 10.5 (12.2) 6.3 (3.02)

0.143 0.086 0.058 0.505 0.036 0.117 0.244 0.527 0.229 0.462

Chi2 t-test t-test t-test t-test t-test t-test t-test t-test t-test

CIRS: Cumulative Illness Rating Score; DAD: Disability Rating Scale; FRS: Functional Rating Scale; NPI: Neuropsychiatric Inventory; MMSE: Mini-mental Status Examination; 3MS: Modified Mini-mental Status Examination. a Reported as mean (std. dev.) except for the dichotomous variable gender.

in the case diagnosed as NFT-predominant dementia. A total of 13 cases had cerebrovascular pathology and/or HS insufficient to contribute to a primary pathological diagnosis. The baseline clinical features for those with and without multiple pathological diagnoses are shown in Table 3. It is important to note that these are baseline characteristics, determined an average of around 5 years prior to autopsy. The MMSE was significantly lower in those with a single pathological diagnosis compared to those with multiple pathological diagnoses although this significance was not corrected for multiple comparisons. There was also a suggestion that those with multiple pathologies were older at the time of clinical assessment than those with only one pathological diagnosis. There were no other significant differences in these baseline features between those with, and those without multiple pathological diagnoses. 4. Discussion We have demonstrated that multiple pathological processes are frequently found in a well-characterized group of patients with a clinical diagnosis of dementia. This has been demonstrated by others [1–3,9,36–39] but these vary in the setting (community, clinic or hospital) and the rigorousness of premorbid assessment of cases and indeed whether they include those only with dementia or a whole sample of individuals irrespective of cognitive status. Furthermore, we have demonstrated that clinical diagnoses generally do not capture all the pathological diagnoses when there is more than one. In only two of 21 cases where there was more than one pathological process regarded as significant were all these correctly reflected in the clinical diagnoses. In two cases with multiple pathological diagnoses, there was a complete mismatch of clinical and pathological diagnoses, although the number is similar to the two cases of diagnostic mismatch in the 24 cases with only a single pathological diagnosis. Of the 37 neuropathologically diagnosed AD cases, additional significant pathology was found in 18 (48.6%) and in a further 10 cases additional pathology of uncertain significance was found (27.0%) giving a total of 75.7% of AD cases with additional pathological findings. This high prevalence of non-AD pathology in AD cases has been shown by others. Autopsies of subjects from the Religious Orders Study and the Rush Memory and Aging Project revealed that 45.8% of people with a diagnosis of probable AD had mixed pathologies, most commonly AD pathology with macroscopic infarcts, neocortical LBs or both [40]. In a community-based autopsy series, only 34 of 94 neuropathologically diagnosed AD cases (36.2%) had AD pathology alone, whereas 63.8% had coexisting CVD or Parkinson’s-related pathology including LBs [41]. If we require the additional pathological findings in our study

to include LBs or any CVD, 27 AD cases (73.0% of all those with a pathological diagnosis of AD) had such additional pathology, not dissimilar to the 63.8% in Lim et al.’s study. If restricted to LB and/or CVD sufficient to lead to a pathological diagnosis, with or without an additional pathological diagnosis, 11 (29.7%) of our neuropathologically diagnosed AD cases had such mixed pathology. However, it is noteworthy that AD does dominate the pathological and clinical diagnoses in our study, and in only two cases with AD pathologically (one with AD alone, the other with AD and FTLD-U) was AD not also diagnosed clinically; in each case, the only clinical diagnosis was FTD. We have demonstrated that additional pathological features, regarded by the pathologist as insufficient to have contributed to dementia, were frequent (n = 33, 53.3% of cases). However, this is a subjective assessment and these findings may still have affected the clinical features of the cases in a more subtle way. It is noteworthy that of the 29 cases with CVD found at autopsy, whether felt pathologically significant or not, in only six cases were these reflected in a clinical diagnosis of VaD (alone or mixed with other clinical diagnoses). The clinical expression of the vascular component in mixed cases is highly dependent on lesion type and location as well as severity of concomitant AD-related pathology [42]. Interestingly, in our study, white matter changes in brain scans were noted in 17 out of 29 at the time of initial assessment, while the clinical diagnosis of VaD was made in only the six cases. The clinical diagnosis of VaD was not made in the other cases (n = 11/17) because of a lack of history of TIA and strokes, or a lack of focal neurological signs. It is possible that some of the CVD developed after their clinical assessments but prior to their autopsy. Only one of the 29 cases with CVD had large vessel ischemic stroke as the only vascular pathology. The lack of a clinical diagnosis of VaD in these cases does support the pathologist’s assessment that in 22 cases these CVD findings were non-contributory. Multiple pathological processes have also been shown in a community autopsy series of those both with and without dementia. In 209 autopsies of subjects in the Medical Research Council Cognitive Function and Aging Study, there was a high frequency of both AD and CVD. Further, the presence of this pathology did not accurately predict whether they had a clinical diagnosis of dementia [38]. In that study, LBs were also evaluated and found in 10.5% of subjects but equally between demented and non-demented subjects (odds ratio 1.4, 95% CI 0.5–3.5). We detected several pathological diagnoses that are not commonly reported on in community studies, including FTLD, PiD and PSP. This may reflect the specialist nature of the dementia diagnostic services in Vancouver, from whom these subjects were recruited – such services do attract more unusual subjects, who are more challenging to diagnose.

M. Woodward et al. / European Geriatric Medicine 1 (2010) 259–265

It is likely that the presence of multiple pathological processes modifies clinical features, making clinical diagnosis more difficult. For instance, the presence of both AD and FTLD pathological diagnoses, found in eight of our patients, was associated with a primary clinical diagnosis of AD in seven cases and FTD alone in the other. This variability in clinical diagnoses may reflect the dominant effect of one of the pathologies, or the sequence in which the pathologies developed. It is conceivable that rather than both pathologies being present when the clinical diagnosis was initially made, the second pathology developed subsequently. This has been suggested in a study of 23 subjects with primary progressive aphasia, where AD pathology was thought to have developed following FTLD pathology [43]. Our study only examined the initial clinical diagnoses whereas the pathological diagnoses were made up to 15 years later. It is quite possible that additional pathology, not present at the time of clinical diagnosis, may have developed and could have led to a change in clinical symptomatology as the disease progressed. It is however difficult in end-stage/severe dementia to clinically differentiate dementia types, as features tend to converge and often subjects move to residential care where reassessments are logistically more problematic. Thus, a gap between final clinical diagnoses and autopsy is frequent in case series such as ours. It is possible that this mismatch of pathological and clinical diagnoses reflects limitations in the criteria for clinical diagnoses. Most are operationalised as a single clinical entity, in turn determined by a single pathological process, with little or no recognition of the possible modifying effects of additional pathologies. Clinicians are thus more likely to make only a single diagnosis, as they did in this study – 33 of the 45 cases had only one clinical diagnosis. Interestingly, the NINCDS-ADRDA criteria for the most common dementia, AD, were derived from cases which we now recognize were highly likely to have had additional pathology, CVD, so these criteria may in part be sensitive to the presence of more than one pathological process. Several previous reports have identified TDP-43 pathology in a high proportion of cases of AD and DLB [11–15]. It is often restricted to limbic structures but sometimes extends into the neocortex and closely resembles the pathology of FTLD-U. We have diagnosed subjects with this extensive TDP-43 pathology as having FTLD-U, but we recognize that this is controversial. It is not clear if the presence of extensive TDP-43 pathology represents a second primary pathological process that might influence the clinical phenotype or a secondary change of little clinical importance. One study found that patients with AD and TDP-43 pathology tend to be older and perform worse on the clinical dementia rating scale, MMSE and Boston naming test [17]. We had eight cases with FTLDU pathology and seven also had AD as a pathological diagnosis. The coexistence of AD and FTLD-U pathology has received little attention, but has been shown by others [44,45]. Some cases clinically diagnosed as AD can present with significant frontal features (usually behavioural) and it is possible that these cases have both pathological processes present [46]. Whether or not the coexistence of FTLD-U like pathology is the substrate for frontal variant, AD has yet to be determined. Although in most of our cases with this combination, the presence of TDP-43 pathology did not appear to affect the clinical presentation, it is interesting that one case was given a pure FTD clinical diagnosis. The clinical significance of multiple pathologies may extend beyond increasing the difficulty of making correct clinical diagnoses. As described in the introduction, multiple pathologies can modify the clinical course of the disease, including increasing the severity of cognitive impairment. It is well recognized that coexisting vascular and AD pathology reduces the amount of AD pathology required for the clinical expression of dementia [4–6]. It has also been shown that the coexistence of AD and DLB pathology

263

is associated with more severe memory deficits than in those with DLB pathology alone [9]. It is surprising, therefore, that we showed significant differences in baseline clinical features between those with only one and those with multiple pathological diagnoses in only one clinical domain (MMSE– and even that may move to marginal significance if adjusted for multiple comparisons) and there was marginal significance in only one other domain (age). Multiple pathologies could be expected to be associated with a lower MMSE at baseline, which is the opposite of our finding, and we would also expect a younger age of onset in those with multiple pathologies, which again was the opposite of our findings. On the other hand, as most of the pathologies we identified have age as their major risk factor, it is not surprising that multiple pathologies accumulated with age. Indeed, the association between the pathological features of AD and dementia has been shown to be stronger in younger old than older old people, demonstrating that a single pathological process is less likely to express as clinical dementia with increasing age [47]. We did not examine subsequent clinical features, but it is possible that the two groups did become different, perhaps as they developed more prominent multiple pathologies. Differences may have become more prominent as the clinical dementia became more advanced, but it is not possible to predict that from our data and, as discussed above, evaluation of the clinical expressions of more advanced dementia can be problematic. It is also possible that the lower MMSE in the single pathology group was due to a higher proportion of cases with conditions that the MMSE is more sensitive to – the subjects with multiple pathologies more frequently included clinical diagnoses that are less well reflected in lower MMSE scores, including vascular dementia (four of 21 cases as opposed to three of 24 in those with single pathology). In our study, a clinical diagnosis of DLB was made in only one of the nine cases where there was significant LB pathology. The high frequency with which the presence of LBs was not diagnosed clinically has been shown by others. In the large MRC-CFAS community study, only 10 of 17 subjects with cortical LBs at autopsy had been diagnosed with any type of dementia, although for all cases in this study, the presence of any dementia-related pathology did not well predict a clinical diagnosis of dementia. In an autopsy series from academic memory clinics, 7% of those with a clinical diagnosis of AD were found to have LBs [48]. New diagnostic criteria for DLB do indicate that where DLB pathology coexists with AD pathology, clinical DLB is less likely to be diagnosed [49]. Our study does support this, as eight of the nine cases with DLB as a pathological diagnosis also had AD as a pathological diagnosis. The overall degree of accuracy suggests that subjects in this study were well evaluated clinically and that, generally, at least one of the clinical diagnoses was reflected in a pathological process. We found only four cases of complete clinical ‘‘misdiagnosis’’, where none of the clinical diagnoses matched any of the pathological diagnoses. One of these cases had a pathological diagnosis of NFT-dementia and it is unclear how that presents clinically. FTD was one clinical diagnosis that was more often not reflected in the pathology. Of the four cases with FTD as the sole clinical diagnosis, two were confirmed pathologically (as PiD), while one had a combination of FTLD-U and AD and the other had only AD pathology. Furthermore, two cases with combined clinical diagnoses of AD and FTD had only AD pathology. Additionally, in only 4/8 cases where VaD was diagnosed clinically was CVD found as a pathological diagnosis although in three of the cases not pathologically diagnosed as CVD-related dementia there was additional cerebrovascular pathology present. It may be that pathological diagnoses should be reexamined as the ‘‘gold standard’’ for dementia diagnosis. We found 26 pathological diagnoses, in 21 subjects that were not reflected in

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any clinical diagnoses. The fact that so many pathological patterns, considered significant by the pathologist, were not reflected in the clinical diagnoses may not simply mean that the clinical diagnoses were wrong or incomplete. Perhaps the pathology was not producing clinically significant symptoms, or other factors may have modified the clinical presentation of the pathology. It is conceivable that AD pathology overshadows other pathological processes. Additionally, the pathology found at autopsy not may have been present at the time of clinical assessment, which often preceded the autopsy by several years. If this is the case, it suggests the brain already affected by a dementia may be prone to then develop additional pathology associated with other dementias. What should be the gold standard – pathology at autopsy or clinical features often last fully characterized years earlier? Furthermore, dementia may arise from the interaction of pathological changes and compensatory mechanisms [45]. Nevertheless, it is worth considering what is more important, the pathology or how it affects an individual clinically. It is disconcerting that postmortem brain pathology rarely seems to fully match the clinical features that were expressed earlier, even in a well-characterized cohort from a center of excellence in AD diagnosis and research. In an era where expensive and potentially toxic diseasemodifying medications are being developed for dementia, accurate diagnosis is increasingly important. Our paper suggests clinical diagnoses are more accurate when there is only one pathological diagnosis, and this is more likely in younger patients and when made early in the progression of the disease. This could have implications for clinical trial design. Approaches that may assist in the recognition of pathologies unexpected clinically include the use of biomarkers and neuroimaging. Biomarkers have been used in distinguishing AD from FTD [50–52] and neuroimaging with MRI techniques may be similarly used [53]. Amyloid imaging with PET may be useful in detecting amyloid plaque [54–56] to confirm a diagnosis of AD or DLB and to exclude FTD. Other PET imaging approaches may help to diagnose DLB but need further evaluation [57,58]. These approaches need to be better correlated with pathology, but if they do indeed provide information akin to an antemortem autopsy, they will be essential in situations where an accurate pathological diagnosis is required – for example, where a potentially disease-modifying agent, targeting a particular pathology, is being trialled. In conclusion, we have demonstrated a high prevalence of multiple pathologies in this exploratory study of subjects with dementia. These multiple pathological processes are rarely all reflected in the clinical diagnoses and are often hard to recognize in the initial clinical presentation. This clinical difficulty in detecting all significant pathologies has important implications for care planning and therapeutic approaches. Conflict of interest statement There are no conflicts of interest for any of the authors that are relevant to the content of this paper. Acknowledgement The authors thank the ACCORD Investigators for their contribution to the methodology on which this single site study is based.Funding: the ACCORD study is funded by CIHR Industrypartnered program grant # PA14197. Sponsorship from the PMAC was obtained from AstraZeneca, Aventis, Bayer, Eli Lilly, GSK, Hoffman Laroche, Janssen, Novartis, and Pfizer Canada Inc. These companies provided funding as a grant in aid and had no input into the design, conduct, collection, management, analysis or interpre-

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