Argyrophilic Grain Pathology in Frontotemporal Lobar Degeneration: Demographic,Clinical,Neuropathological,and Genetic Features

Abstract

Frontotemporal lobar degeneration (FTLD) is a clinically, pathologically, and genetically heterogeneous group of disorders that affect the frontal and temporal lobes of the brain. FTLD classification distinguishes three main neuropathological groups: FTLD-tau, FTLD-TDP, and FTLD-FUS. As a four-repeat tauopathy, argyrophilic grain disease (AGD) is included in the FTLD-tau group. AGD may also appear in association with other neuropathological disorders. We describe the demographic, clinical, neuropathological, and genetic characteristics of a series of FTLD cases presenting with AGD. For this purpose, a clinico-pathological study of 71 autopsy-confirmed FTLD cases from different tissue banks was performed. AGD was found in 52.1% of FTLD cases. The presence of AGD increased with the increasing age (up to 88.9% in cases older than 80 years; p < 0.001) and was associated with higher ages at onset (p < 0.001) and death (p < 0.001). In AGD cases, progressive supranuclear palsy (PSP) was the most frequent clinical diagnosis (29.7%) and gait disturbance was the most common symptom (64.5%); behavioral and language symptoms were less frequent as compared with non-AGD cases (p = 0.055; p = 0.012). PSP was the most frequent neuropathological diagnosis among cases with AGD (32.4%). This group also showed less brain atrophy (p = 0.094) and higher prevalence of Alzheimer (p = 0.002) and vascular pathology (p = 0.047) as compared to the non-AGD group. We also observed that H1/H1 genotype was overrepresented in AGD cases (p = 0.018) and that there was no association with any specific APOE allele. A subanalysis of PSP cases according to the AGD status was carried out, yielding no significant differences.

Keywords

Argyrophilic grain disease frontotemporal dementia frontotemporal lobar degeneration tauopathy

INTRODUCTION

Frontotemporal lobar degeneration (FTLD) is a clinically, pathologically, and genetically heterogeneous group of disorders that affect the frontal and temporal lobes of the brain. The subtypes of underlying pathological changes in patients with FTD are classified on the basis of the pattern of protein deposition into three main categories [1, 2]: FTLD with tau pathology (FTLD-Tau), FTD associated with TAR DNA binding protein-43 (FTLD-TDP) and FTLD associated with fusion protein in sarcoma (FTLD-FUS). FTLD-Tau includes different tauopathies, mainly Pick’s disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and argyrophilic grain disease (AGD).

AGD was first described as a neurodegenerative disease characterized by small spindle-shaped stain-positive structures called argyrophilic grains (AGs) in the neuropil of the hippocampus, entorhinal cortex and other limbic structures [3, 4]. Since a four-repeat tauopathy, AGD is included in the FTLD-tau group. AGD pathology is often accompanied by varying degrees of Alzheimer-type pathology [5] and it can also be found in other neuropathological disorders, including other tauopathies and Lewy body disease [5, 6].

According to the literature, AGD pathology is found in 5–10% of consecutive autopsies [7] rising to over 40% when the very early stage of AGD is included [8]. Although AGD is therefore not a rare pathological entity, only few studies have dealt with the clinical features of AGD. These studies reported a slow progressive cognitive decline and memory disturbances [9, 10]. Furthermore, it has been reported an abnormal behavior with personality changes, presenting as a behavioral-variant of frontotemporal dementia [11, 12] and psychiatric symptoms [13]. These symptoms are often generated synergistically with other concomitant pathologies (principally Alzheimer and vascular pathology) [14, 15]. Thus, AGD as the only pathological substrate is a rare condition [10, 14].

The frequency of microtubule-associated protein tau (MAPT) H1/H1 genotype tends to be higher in AGD as 4R tauopathy [8]. The apolipoprotein E (APOE) ɛ4 carrier state is lower than in Alzheimer’s disease (AD), while the prevalence of the ɛ2 allele is higher in AGD [7].

Although the relationship between AGD and AD and other neurodegenerative diseases is well known, the presence of AGD in FTLD has not been studied to the best of our knowledge. The aim of this study is to analyze the demographic, clinical, neuropathological, and genetic characteristics of AGD within a series of FTLD.

MATERIAL AND METHODS

Subjects

Postmortem neuropathological and clinical data were obtained retrospectively from 71 cases with FTLD diagnosis according to the Consensus Criteria of the Consortium for Frontotemporal Lobar Degeneration proposed by Cairns et al. [1]. The whole series was divided into three groups depending on the main neuropathologic diagnosis: FTLD-tau, FTLD-TDP, and FTLD-FUS. FTLD-tau cases were further subclassified into 7 groups: PSP, CBD, PiD, other-FTLD-tau, AGD+Alzheimer, AGD+vascular, and AGD+others. These last three groups were defined in this way because they mainly presented AGD pathology combined in a lesser degree with Alzheimer and vascular pathology. An analysis was performed according to the presence or absence of argyrophilic grain pathology (AGD, n = 37; non-AGD, n = 34).

Cases were collected, processed and provided by three different neurological tissue banks (Banco de Tejidos CIEN [BT-CIEN, n = 44], Banco de Cerebros de la Region de Murcia [BCRM, n = 14] and Banco de Tejidos para Investigación Neurológica/Hospital Universitario Fundación Alcorcón [BTIN/HUFA, n = 13]) between 2003 and 2014. These three neurological tissue banks are integrated in the Spanish Biobanks Network (http://www.redbiobancos.es) and registered on the Registro Nacional de Biobancos. The material was processed following standard operating procedures with appropriate approval of the Ethical and Scientific Committees.

Clinical information

Age of onset of symptoms, age at death, disease duration and sex were systematically recorded. Data were also collected on prior medical history, cardiovascular risk factors (hypertension, dyslipidemia, diabetes, smoking, alcohol use, and stroke), family history of dementia or psychiatric illness, clinical suspicion, first symptom of disease and occurrence of other neurological symptoms during the course of the disease (memory impairment, language or behavior symptoms, parkinsonism, supranuclear gaze palsy, and gait disturbance).

Standard neuropathological procedure

Postmortem examination was made according to the brain bank protocol and limited to the cranial cavity [16]. Atrophy was analyzed on the whole sample of the brain by means of macroscopical visual examination. A full neuropathological study was performed in the left half brain by obtaining 25 tissue blocks from cortical and subcortical regions after fixation. Neuropathological classification was based on the examination of hematoxylin-eosin stained paraffin sections of all blocks, and immunostaining with a panel of antibodies (Aβ, Tau, AT100, alpha-synuclein, ubiquitin, and TDP-43). Consensus criteria were used for disease diagnosis and staging [17].

Argyrophilic grain pathology

AGD pathology was assessed in paraffin sections of the left brain hemisphere at three coronal (anterior–posterior) levels of the medial temporal lobe: 1) level 1 (L1) corresponds to a mid-coronal plane of the amygdala including the adjoining entorhinal and perirhinal cortices, 2) level 2 (L2) includes the anterior segment of the hippocampus, the entorhinal cortex and the medial and lateral banks of the collateral sulcus, and 3) level 3 (L3) is homologous to L2 at a posterior coronal plane, and includes the anterior segment of the body of the hippocampus together with the adjoining cortices, including the collateral sulcus [15]. In each block, consecutive paraffin sections were immunostained with AT8, AT100 (1 : 100, Innogenetics, Gent, Belgium) and p62 (Thermo Fisher Scientific Inc.,Waltham, Massachusetts) primary antibodies.

The frequency of AGs, pretangles (pNFT) and neurofibrillary tangles (NFT) was assessed by a semiquantitative score (0–3), which was obtained in multiple areas at each coronal level: nuclei of the amygdala (L1), entorhinal/transentorhinal cortex (L1-2), perirhinal cortex (L1-3), subiculum (L2-3), CA1 (L2-3), CA2-3 (L2-3) and dentate gyrus (L3). AG frequency was also analyzed in extratemporal regions: posterior hypothalamus, nucleus accumbens, anterior insular and cyngulate cortex and brainstem tegmentum [15, 18].

Alzheimer and vascular pathology

AD-type pathology was assessed following the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) protocol which analyzes neurofibrillary changes according to the Braak staging system [19, 20].

Cerebrovascular lesions were analyzed with a vascular pathology (VP) protocol designed for the assessment of small vessel pathology in frontal and temporal lobes (scoring 0–6 each), basal ganglia and hippocampus (scoring 0–4 each), yielding a total VP index (scoring 0–20) [21, 22]. The assessment of VP was performed on hematoxylin-eosin stained tissue sections. Multiple tissue blocks were included in the assessment of a single VP item (frontal, temporal, and basal ganglia) and it was selected the highest score obtained for each area. Other relevant neuropathological findings were also recorded (e.g., hippocampal sclerosis and Lewy type pathology).

Genotyping

Analyses of MAPT and APOE polymorphisms were carried on for 51 cases. Samples were not available in all cases due to the retrospective design of the study. Total deoxyribonucleic acid (DNA) was isolated from cerebral tissue following standard procedures. Genotyping of MAPT rs1052553 polymorphism, which discriminates between MAPT H1 and H2 haplotypes, was performed using TaqMan^® probes (C 7563736 10 assay, Applied Biosystems), according to manufacturer’s instructions. APOE genotyping (rs429358 and rs7412) was performed by Real-Time Polymerase Chain Reaction (PCR) [23]. Published data from H1 and H2 prevalence in the normal Spanish population were used as a comparative group [24, 25] as well as data of the Vallecas Project, an ongoing longitudinal study on aged subjects without neurological disease (n = 694; age range: 68–85 years; M/F ratio, 1 : 1.87; Fundación CIEN, Madrid, Spain) [16]. Control data for the analysis of APOE were also obtained from the Vallecas Project (n = 1147). The odds ratio (OR) and the significance value were obtained through the χ² statistic by using GraphPad Prism v4 program. Hardy-Weinberg equilibrium of the genotype distributions of control populations was determined by means of the analysis of the distribution of observed versus expected genotype frequencies. The level of significance was based on a χ² distribution with one degree of freedom. Our study did not include the assessment of any genetic mutations related to FTLD (MAPT, microtubule associated protein; GRN, progranulin, and C90RF72) [2].

Statistical analysis

Statistical analyses were performed using the SPSS computer software (SPSS v21) with an α set at 0.05 (two-tailed). Descriptive statistics were used to characterize the demographics of the cohort. All binary data were compared across groups with the Pearson’s χ² test. Fisher’s exact test was used for any analysis with small numbers. Analysis of variance (ANOVA) and Kruskal-Wallis tests were performed across all groups for analyses of continuous data and, when significant, were followed by Mann-Whitney U-test comparisons across two groups. Spearman’s rho was used to examine correlations between clinical and pathological variables. Since this was intended to be an exploratory analysis, no adjustment for multiple comparisons was made.

RESULTS

In the whole sample, the mean age at death was 74.8 years (standard deviation, SD, 11.2) and the age at onset was 66.6 years (SD 10.9). The median time of the disease was 7 years and 56.3% were men.

Among the 71 FLTD cases, 52 were classified as FTLD-tau (73%), 18 as FTLD-TDP (25%) and one was FTLD-FUS (2%). Within the FTLD-tau group, the cases were divided into the following subgroups: PSP (n = 17; 23.9%), CBD (n = 8; 11.2%), PiD (n = 7; 9.8%), AGD+Alzheimer (n = 7; 9.8%), other-FTLD-tau (n = 6; 8.4%), AGD+vascular (n = 4; 5.6%) and AGD+others (n = 3; 4.2%).

AGD versus non-AGD

AGD pathology was identified in 52.1% of the sample (n = 37). The proportion of women was lower in the AGD group than in the non-AGD group (45.9% versus 67.6%; respectively, p = 0.06; see Table 1). AGD pathology was associated with higher ages at onset (p < 0.001) and death (p < 0.001). Figure 1 shows the presence of AGD, which increases with the increasing age, reaching a value of 89% in cases older than 80 years (p < 0.001).

Table 1

Characteristics of the whole sample of FTLD by AGD status (n = 71)

	AGD (n = 37)	Non-AGD (n = 34)	p
Demographic features
Female, n (%)	17 (45.9)	23 (67.6)	0.064
Age at death, mean (SD)	78 (8.2)	69.3 (11.2)	<0.001
Age at onset, mean (SD)	71.2 (8.7)	62.4 (11)	<0.001
Time of disease, mean (SD)	6.7 (4.1)	7 (4.9)	0.832
Cardiovascular risk factors, n (%)
Hypertension	16 (50)	8 (25.8)	0.048
Dyslipidemia	10 (31.3)	5 (16.1)	0.159
Diabetes mellitus	3 (9.4)	7 (22.6)	0.152
Smoking	12 (37.5)	8 (25.8)	0.319
Alcohol use	2 (5.4)	2 (5.9)	0.931
Traumatic brain injury	1 (3.1)	0 (0)	0.321
Psychiatric illness	6 (18.8)	5 (16.1)	0.784
Stroke	2 (6.3)	1 (3.2)	0.573
Symptoms, n (%)
Memory impairment	27 (52.9)	24 (47.1)	0.979
Behavior disturbance	20 (44.4)	25 (55.6)	0.055
Language	13 (37.1)	22 (62.9)	0.012
Parkinsonism	21 (56.8)	16 (43.2)	0.128
Supranuclear gaze palsy	10 (58.8)	7 (41.2)	0.431
Gait disturbance	20 (64.5)	11 (35.5)	0.023
Neuropathology
Brain weight (mg), mean (SD)	1085.7 (134.5)	1017 (223.1)	0.094
Alzheimer pathology (tau Braak stage), n (%)	15 (83.3)	3 (16.7)	0.002
Vascular pathology, n (%)	15 (71.4)	6 (28.6)	0.047
VP index, mean (SD)	6.8 (2.7)	5 (1.9)	0.006
H1/H2 MAPT, n (%)
H1/H1	23 (64.9)	11 (35.3)	0.018
H1/H2	6 (18.9)	12 (38.2)
APOE, n (%)
ɛ2/ɛ3	5 (13.5)	4 (11.8)	0.136
ɛ3/ɛ3	21 (59.5)	13 (41.2)
ɛ3/ɛ4	3 (8.1)	4 (11.8)
ɛ4/ɛ4	0	2 (5.9)

AGD, argyrophilic grain disease; APOE, apolipoprotein E; FTLD, frontotemporal lobar degeneration; VP, vascular pathology; MAPT, microtubule associated protein; SD, standard deviation; ^£Fisher exact test; ^¥Pearson chi-square; *Student t test.

PSP was the most frequent clinical diagnosis in the AGD group (n = 11; 29.7%). On the one hand, the most common symptom in AGD cases was gait disturbance (64.5%, p = 0.023) followed by supranuclear gaze palsy (58.8%, p = 0.431). On the other hand, behavioral and language symptoms were less frequent (p = 0.055 and p = 0.012). Moreover, regarding cardiovascular risk factors, the presence of hypertension was more frequent in AGD group (p = 0.048, see Table 1). No difference was observed in the rest of cardiovascular risk factors.

PSP was the most frequent neuropathological diagnosis in AGD cases (n = 11; 32.4%; Table 2). Brain atrophy was lower in AGD cases (p = 0.094). Frequency of AGs assessed by a 0–3 score showed that grade 3 was predominant (n = 12; 18.5%), grade 2 was observed in 15.4% (n = 19) and grade 1 and 4 were observed in 6.2% (n = 4). Regarding AD and VP analyses, AGD group showed a higher proportion of both of them. AD type pathology showed a moderate to high tau Braak stage (p = 0.002), whilst in the case of VP, a total value of p = 0.047 and a higher microscopic VP index (p = 0.006) were observed. Adjusting by age, a major degree of Alzheimer pathology and VP was observed with the increasing age, obtaining values of Braak tau = 2.63 (mean) and VP index = 7.2 (mean) in cases older than 80 years. Hippocampal sclerosis was present in only a few cases (21.6% of the whole series) and was not included in this analysis.

Upon genetic polymorphism analysis, the frequency of the MAPT H1/H1 genotype was higher in AGD cases (64.9% versus 35.3%; p = 0.018). For the APOE gene, the ɛ3/ɛ3 haplotype was predominant in both the AGD and non-AGD groups (59.5% and 41.2%, respectively), while the presence of APOE4 was quite low. There was no association between APOE genotype and AGD status.

AGD in PSP cases

In order to evaluate the influence of AGD pathology in PSP cases, a subanalysis of all the PSP cases (with and without AGD pathology) was performed, as shown in Table 3. Among total PSP cases (n = 17), those with AGD pathology (n = 11) tended to have higher ages at onset and death and longer time of disease (non-significant). From a clinical point of view, parkinsonian symptoms were the most frequent in AGD-PSP cases, followed by gait disturbance and supranuclear gaze palsy (no significant differences).

Fig.1

Proportion of cases with argyrophilic grain disease (AGD) for each age group.

Concerning AD pathology, it was observed a greater proportion in AGD-PSP cases (p = 0.675). On the contrary, VP was more frequent in non AGD-PSP cases (p = 0.182). In polymorphism analysis, all AGD-PSP available cases were H1/H1 (p = 0.12). ɛ3/ɛ3 was the most common haplotype for the APOE gene in both groups (54.5% and 50%, respectively).

DISCUSSION

In this study we analyzed 71 cases from a clinical-pathological FTLD series to investigate possible distinctive demographic, clinical, neuropathological and genetic features associated with AGD pathology. The prevalence of AGD in the current series (52.1%) is higher than in other studies, as reported in [5 , 27] including Josephs et al. [14], who identified AGD in 16% of 359 autopsy cases from a dementia clinic (age range 74–101 years). Martinez-Lage and Muñoz [6] observed that the prevalence of AGD was 6% in 300 unselected consecutive autopsies of patients older than 30 years, but only 12% in those older than 65 years, reaching 31% in centenarians. In the case of FTLD, we have not found previous studies in the literature, which report the prevalence of AGD.

Table 2

Distribution of AGD cases according to neuropathological diagnosis

Neuropathological diagnosis	n	%
PiD	1	2.7
PSP	11	32.4
CBD	6	16.2
Other-FTLD-tau	3	8.1
FTLD-TDP	2	5.4
FUS	1	2.7
AGD+ALZH	7	18.9
AGD+VASC	4	10.8
AGD+Other	3	8.1

AGD, argyrophilic grain disease; AGD+ALZH, argyrophilic grain disease-Alzheimer; AGD+VASC, argyrophilic grain disease-vascular; AGD+other, argyrophilic grain disease- other; CBD, corticobasal degeneration; FTLD-tau, frontotemporal lobar degeneration with tau pathology; FTLD-TDP, frontotemporal lobar degeneration associated with TAR-ADN binding protein-43; FUS, fused in sarcoma protein; PiD, Pick disease; PSP, progressive supranuclear palsy.

Table 3

Characteristics of PSP cases by AGD Status (n = 17)

	PSP+/AGD+ (n = 11)	PSP+/AGD- (n = 6)	p
Demographic features
Age at death, mean (SD)	76.9 (6,9)	66.2 (10.6)	0.191
Age at onset, mean (SD)	68.7 (7)	60 (9.5)	0.365
Time of disease, mean (SD)	7.8 (4.6)	6.2 (1.3)	0.155
Female, n (%)	7 (63.66)	4 (36.4)	0.900
Cardiovascular risk factors, n (%)
Hypertension	5 (50)	2 (40)	0.714
Dyslipidemia	3 (30)	1 (20)	0.680
Diabetes mellitus	2 (40)	2 (40)	0.409
Smoking	5 (50)	2 (40)	0.714
Alcohol use	0 (0)	1 (16.7)	0.163
Traumatic brain injury	5 (100)	5 (100)	–
Psychiatric illness	1 (10)	1 (20)	0.591
Stroke	0 (0)	1 (20)	0.143
Symptoms, n (%)
Memory impairment	8 (66.7)	4 (33.3)	0.752
Behavior disturbance	8 (80)	2 (20)	0.417
Language	4 (57.1)	3 (42.9)	0.377
Parkinsonism	10 (71.4)	4 (28.6)	0.554
Supranuclear gaze palsy	9 (75)	3 (25)	0.774
Gait disturbance	10 (71.4)	4 (28.6)	0.554
Neuropathology
Brain weight (mg), mean (SD)	1124.4 (160.8)	1191.4 (176.2)	0.291
Alzheimer pathology (tau Braak stage), n (%)	3 (75)	1 (25)	0.675
Vascular pathology, n (%)	1 (33.1)	3 (66.7)	0.182
VP index, mean (SD)	5 (1.4)	4.4 (2.5)	0.587
H1/H2 MAPT, n (%)
H1/H1	72.7 (8)	∼66.6 (4)	0.12
H1/H2	0	0
APOE, n (%)
ɛ2/ɛ3	6 (18.2)	0	0.140
ɛ3/ɛ3	2 (54.5)	3 (50)
ɛ3/ɛ4	0	1 (16.6)

AGD, argyrophilic grain disease; APOE, apolipoprotein E; VP, vascular pathology; MAPT, microtubule associated protein; PSP, progressive supranuclear palsy; SD, standard deviation; ^£Fisher exact test; ^¥Pearson chi-square.; ^*Student t test.

AGD often appears in combination with other degenerative changes, mainly with PSP and AD pathology. The frequent combination with other 4R tauopathies—especially with PSP—is well documented, ranging from 18.8% to 80% in several early studies [6, 7]. Recently, Tatsumi et al. [28] reported that eight out of 30 PSP cases (26.7%) had AGD. However, “pure AGD cases” are infrequent [9, 14].

In our series, a gradual increase of AGD frequency with age is observed (Fig. 1). This has previously been documented in several studies, from 5% or under in cases 50–60 years old to over 10% in cases aged 70 years or older [5]. AGD presence is related to advanced ages, both at the beginning and the end of the disease. On the one hand, in the series of AGD cases described by Josephs et al. [14] the mean age at death was 90 years, whereas the mean age at onset was 87 years. On the other hand, previous reports stated that the disease begins between 75–80 years [29 , 31]. These disagreements between different series might be due to the different distribution of age of the cases, though they can also derive from different criteria of inclusion, mainly in the initial stages of AGD.

Regarding clinical manifestations, AGD cases presented a major proportion of parkinsonian symptoms, although only gait alteration with falls turned out to be significant, probably related to a major proportion of PSP cases in our sample (32.4%), see Ref. [32]. Language and behavioral alterations were less frequently observed in cases with AGD. This is in contrast with former series, in which the behavioral alteration was a common symptom of AGD, probably due to the aggregation of AGD in the structures of the limbic system [27]. Our analyses of AGD pathology in PSP cases did not show significant differences between subgroups (with or without AGD). This confirms that the presence of AGD in PSP cases does not affect neither in the clinic nor in the disease evolution.

In the current series, AGD cases were associated with a major degree of AD and VP, which could be related to an older age of these cases, since it has been observed in other series [33]. Overlapping between AGD and both AD and VP is a common finding, so neurofibrillary, Aβ and vascular pathology could have a role in the cognitive decline [34].

The H1/H1 genotype was more frequent in AGD compared to non-AGD cases, particularly in PSP-AGD cases (100%). Previous studies have reported an association between this haplotype in the tau gene and PSP [35, 36], which is also characterized by neuronal accumulation of tau protein. Verpillat et al. [37] found an association between the H1/H1genotype of the tau gene and FTD compared with controls (62% versus 46%, p = 0.01), confirming the primary role of tau in FTD. In a similar way, Lladó et al. [38] evaluated the 4R/3R tau mRNA ratio in 18 patients with FTLD and the effect of the H1/H1 genotype on this ratio. They observed a significant increase in the 4R/3R mRNA ratio, which suggested that this genotype could modulate the tau mRNA splicing. Nevertheless, the pathogenic mechanism by which the H1/H1 genotype causes an increased risk for some tauopathies is unknown. Subtle changes in the regulation of tau expression or alternative splicing could be one of the underlying mechanisms. With regards to APOE analysis, we failed to find an association between AGD and a specific APOE alleles, in line with most of the previous studies [5 , 40].

This study was limited by the lack of complete medical history data and its cross-sectional, retrospective design. AGD pathology was analyzed in a sample of FTLD cases, excluding other degenerative disorders as AD, Lewy body disease, or CBD also related to AGD. This fact might be a limitation of the study. Data related to parkinsonian symptoms in PSP could also suppose a bias of the study without a stratified analysis of cases. Despite these limitations, it has considerable strengths. To the best of our knowledge, this is the first study that examines demographic, clinical, neuropathological and genetic features of AGD in FTLD.

In conclusion, AGD in FTLD cases is associated with older age, longer time of disease and clinical diagnosis of PSP. AGD is often accompanied by varying degrees of Alzheimer and vascular pathology and it rarely occurred as an isolated neuropathological finding. Comorbidity of AGD and other degenerative changes might reflect a certain pathogenic relationship but it is still unclear. Clinicians should consider the possibility that coexisting AGD might affect clinical features in other degenerative diseases. Considering that PSP-like subcortical tau pathologies are often found in AGD cases, it should be explored whether the combination of AGD pathology has an impact not only in the cognitive domain but also in motor function in patients with PSP. Prospective clinical-pathological studies are needed to investigate the neuronal basis of clinical changes in AGD.

Footnotes

ACKNOWLEDGMENTS

We are particularly grateful for the generous contribution of the patients and the collaboration of the three Biobanks: Banco de Tejidos CIEN, Biobank Network of the Region de Murcia (BIOBANC-MUR) and Banco de Tejidos Fundación Alcorcón, all of them integrated in the Spanish Network and registered on the Registro Nacional de Biobancos and supported by the Instituto de Salud Carlos III.

We thank all the families for their support and generous donation of brain tissue.

We wish to express our acknowledgement to E. Gómez (BT-CIEN), V. Martínez, L. Peyres (BCRM) and A. B. Rebolledo (BTIN/HUFA) for their technical work, and to C. Guerrero (BTIN/HUFA) for her assistance in neuropathological diagnosis.

Authors’ disclosures available online ().

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