Aging and cerebrovascular lesions in pure and in mixed neurodegenerative and vascular dementia brains: a neuropathological study

Introduction

The prevalence of dementia is increasing in our aging population. Because of the complexity of disease pathology, dementia classifications remain controversial [32]. Many distinct brain diseases other than Alzheimer’s disease (AD) afflict older human patients and contribute to cognitive impairment [2,31]. Dementia of unknown aetiology increases with age [8]. Mixed brain pathologies account for most dementia cases in the elderly [25,34]. The most common mixed dementia is the coexistence of AD with cerebrovascular pathology [26]. Cerebral amyloid angiopathy (CAA) occurs with increasing age and is the cause that contributes most to this type of mixed dementia [25,27]. The second most frequent mixed dementia is the association of AD with Lewy body disease (LBD) [26]. Cerebrovascular lesions are also frequently observed in this type of mixed dementia [17,35].
The present post-mortem study investigates whether there are age differences between dementia brains with a single “pure” neurodegenerative or cerebrovascular disease and those with mixed pathological features. Also, the impact of cerebrovascular lesions is compared in the different pure and mixed disease entities.

Material and methods

A total of 216 demented patients, who had been followed up at the Lille University Hospital, underwent an autopsy. Early obtained informed consent of the patients, or from the closest family later, allowed the autopsy for diagnostic and scientific purposes. The brain tissue samples were acquired from the Neuro-Bank of Lille University, federated to the “Centre des Resources Biologiques”, which acted as an institutional review board.
In total, 132 brains with a pure neurodegenerative or cerebrovascular disease and 84 with mixed features were examined. Main age and gender distribution were compared between the overall pure groups and between the most common subgroups according to their main diagnosis. The low number of patients with progressive supranuclear paralysis (PSP), amyotrophic lateral sclerosis (ALS) and corticobasal degeneration (CBD) did not allow a separate statistical comparison between the pure and the mixed cases. Table I shows the percentage distribution of the different types of mixed dementia.
Alzheimer’s disease features were classified ac­cording to the Braak and Braak criteria [3]. The main diagnosis of AD was retained when stages V and VI were reached. In mixed dementia groups, beneath the main diagnosis, additional AD features were retained when stages II to IV were already reached. The CERAD criteria were used to evaluate the severity of CAA [20]. The degree of CAA was evaluated semi-quantitatively on four cortical samples and graded from 0 to 3. The post-mortem diagnosis of frontotemporal lobar disease (FTLD) was made according to the neuropathological diagnostic and the nosological criteria of the Consortium for FTLD [5]. FUS histochemistry was performed in tau- and TDP-negative cases. LBD was diagnosed according to the report of the consortium on DLB international workshop [31]. Progressive supranuclear palsy (PSP) was retained according to the NIND criteria [22]. The neuropathological criteria proposed by Cruz-Sánchez et al. were used for the diagnosis of ALS [7]. The diagnosis of CBD was made according to the recommendations of an international consortium group [1]. Staging of the cerebrovascular pathology in pure and mixed vascular dementia (VaD) was performed according to the recommendations of the vascular dementia group [30].
In addition to the detection of macroscopic visible lesions such as haematomas, and territorial and lacunar infarcts, a whole coronal section of a cerebral hemisphere, at the level of the mamillary body, was taken for semi-quantitative microscopic evaluation of the small cerebrovascular lesions such as white matter changes (WMCs), cortical micro-bleeds (CoMBs), cortical micro-infarcts (CoMIs), and lacunes. The mean values of WMCs were the average of the ranking scores: no change (R0), a few isolated (R1), frequently scattered in the corona radiata (R2), and forming confluent lesions (R3) of myelin and axonal loss. For the other cerebro­vascular lesions their mean values corresponded to their average numbers in the individual brains [21].
Univariate comparisons of unpaired groups were performed with the Fisher’s exact test for categorical data. The non-parametric Mann-Whitney U-test was used to compare continuous variables. The significance level, two-tailed, was set at ≤ 0.05 for moderately significant, at ≤ 0.01 for significant, and at ≤ 0.001 for highly significant.

Results

Overall, patients with mixed dementia were, at death, significantly older than those with pure de­men­tia, with 77 (SD = 10) years in the former and with 72 (SD = 11) years in the latter group (p ≤ 0.01), while male gender distribution was similar: 52% compared to 57%. According to the age distribution, the mixed group consisted mainly of the oldest old (p ≤ 0.05), while adults were more frequent in the pure group (p ≤ 0.05). According to the main diagnosis FTLD was more common in the pure group (p ≤ 0.05) and LBD in the mixed group (p ≤ 0.01). The mixed dementia cases were mainly composed of an association of AD with VaD and with LBD features. By comparing the cerebrovascular lesions between the overall pure and mixed groups, CAA (p ≤ 0.001) was found to be more severe and territorial infarcts (p ≤ 0.01), lobar haematomas (p ≤ 0.01), and CoMIs (p ≤ 0.01) were more frequent in the latter group (Table II).
Comparing age and gender distribution in the subgroups, the main age of the mixed AD group was greater than that of the pure group with, respectively, 77 (SD = 10) years and 69 (SD = 10) years (p ≤ 0.001), predominantly in the middle old group (p ≤ 0.0.5). A similar age difference was observed between the FTLD groups with, respectively, 87 (SD = 6) and 66 (SD = 10) years (p ≤ 0.001). Also, according to the age classification, mixed FTLD occurred more frequently in the middle and oldest old patients (p ≤ 0.05) and more in the adult and the young old of the pure group (p ≤ 0.001). No average age differences were observed between the pure and the mixed LBD, with, respectively, 78 (SD = 3) years and 81 (SD = 7) years, predominantly in the middle and oldest old of both groups. Also, in VaD no age differences were observed, with 76 (SD = 7) years in the pure and 77 (SD = 19) years in the mixed cases. Gender distribution was similar in all the disease subgroups, except for the pure AD patients, in which a male predominance was seen (p ≤ 0.05) (Table III).
The neuropathological examination revealed an increased severity of CAA (p ≤ 0.001) and of territorial infarcts (p ≤ 0.01), lobar haematomas (p ≤ 0.01), and CoMIs (p ≤ 0.001) in the mixed AD group with no differences in the severity of lacunar infarcts, WMCs, and CoMBs. In FTLD only CoMIs were increased in the mixed group (p ≤ 0.05). In LBD no differences in severity of all cerebrovascular lesions were observed. In pure VaD the number of lacunar infarcts was significantly increased (p ≤ 0.01) while CAA predominated in the mixed form (p ≤ 0.001) (Table IV).

Discussion

The present study confirms that, overall, patients with mixed dementia are older than those with a pure neurodegenerative or cerebrovascular disease [24]. However, there are differences according to the disease type: mainly patients with AD and FTLD, who are the most frequent in this series, display this age difference, but not those with LBD and VaD.
AD with VaD or LBD features are the most frequent types of mixed dementia [4,17,28].
The increase of CAA with age is the leading cause of mixed AD group in elderly patients, leading to more frequent cerebral infarcts and lobar haematomas [10,14,16-18,21,24].
Brains with FTLD display a low incidence of cerebrovascular lesions [11]. The reason why patients with FTLD and ALS have a favourable vascular risk profile is unknown [19]. The severe frontotemporal WMCs are related to the neurodegenerative disease itself and are not of vascular origin [12]. The increased number of CoMIs in the mixed form, compared to the pure form of FTLD, is probably related to the much older age of the former [6].
Our study confirms that pure and mixed forms of LBD mainly occur in the middle old and the oldest old patients [34]. Pure and mixed LBD brains show a high incidence of CoMIs [14,17]. Additional AD features and CAA contribute less to the small cerebrovascular in LBD pathology [13,15,35].
Different types of cerebrovascular lesions have already been described in pure VaD and mixed AD-VaD brains, with mainly lacunar infarcts in the former and severe CAA in the latter [16,17].
In conclusion, the older age of mixed dementia cases is mainly due the combination of the severity of the AD and LBD pathologies, and to CAA-related cerebrovascular lesions. This study argues again that mixed AD-VaD has to be considered as the end stage of AD [16].

Disclosure

The authors report no conflict of interest.

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