







































Increased frontocortical microvascular raspberry density in frontotemporal lobar degeneration compared to Lewy body disease and control cases: a neuropathological study


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Increased frontocortical microvascular raspberry density in  
frontotemporal lobar degeneration compared to Lewy body  
disease and control cases: a neuropathological study 

Henric Ek Olofsson¹, Elisabet Englund¹ 

1 Division of Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden 

Corresponding author: 
Henric Ek Olofsson · Department of Clinical Sciences Lund · Lund University · Sölvegatan 25B · Lund, 22362 · Sweden 
henric.ek_olofsson@med.lu.se 

Submitted: 01 January 2025 · Accepted: 20 February 2025 · Copyedited by: Lauren Walker · Published: 04 March 2025 

Abstract 

Background: Brain raspberries are histologically defined microvascular entities that are highly prevalent in the 
neocortex. Increased cortical raspberry density occurs in vascular dementia, but also with advancing age. Here, 
we examined the raspberry density in two neurodegenerative diseases, wherein vascular alterations distinct 
from conventional vascular risk factors have been indicated: frontotemporal lobar degeneration (FTLD) and Lewy 
body disease (LBD). 
Methods: This retrospective study included 283 clinically autopsied individuals: 105 control cases without  
neurodegenerative disease, 98 FTLD cases (mainly FTLD-tau and FTLD-TDP), and 80 LBD cases (mainly  
neocortical). The raspberry density was quantified on haematoxylin-eosin-stained tissue sections from the 
frontal cortex, and the frontocortical atrophy was ranked 0–3. 
Results: There was a higher raspberry density in the FTLD group compared to both other groups (P ≤ 0.001; 
Games-Howell post hoc test). The difference between the FTLD and LBD groups remained significant in multiple 
linear regression models that included age, sex, and either brain weight (P = 0.034) or cortical atrophy (P = 0.012). 
The difference between the FTLD and control groups remained significant when including age, sex, and brain 
weight in the model (P = 0.004), while a trend towards significance was demonstrated when including age, sex, 
and cortical atrophy (P = 0.054). Further analyses of the FTLD group revealed a trend towards a positive  
correlation between raspberry density and cortical atrophy (P = 0.062; Spearman rank correlation). Comparisons 
of FTLD subgroups were inconclusive. 
Conclusion: The frontocortical raspberry density is increased in FTLD. An examination of the raspberry density in 
relation to a quantitative measure of cortical atrophy is motivated to validate the results. Future studies are 
needed to determine whether increased raspberry density in FTLD could function as a marker for more  
widespread vascular alterations, and to elucidate the relation between microvascular alterations and neuro-
degenerative disease. 
 

Keywords: Angiogenesis, Cerebrovascular disorders, Frontotemporal lobar degeneration, Lewy body disease, Neurodegenerative  
diseases 

Original Paper 

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mailto:henric.ek_olofsson@med.lu.se


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Abbreviations 

C9orf72 - chromosome 9 open reading frame 
72 gene, CBD - corticobasal degeneration, FTD - 
frontotemporal dementia, FTLD - frontotemporal  
lobar degeneration, FUS - fused in sarcoma, GRN - 
progranulin gene, LBD - Lewy body disease, MAPT - 
microtubule-associated protein tau gene, NFT -  
neurofibrillary tangle, NOS - not otherwise specified, 
PiD - Pick’s disease, PSP - progressive supranuclear 
palsy, TDP-43 - transactivation response DNA-bind-
ing protein 43, UPS - ubiquitin proteasome system. 

Introduction 

Frontotemporal lobar degeneration (FTLD) and 
Lewy body disease (LBD) are two heterogeneous 
neuropathological entities that manifest with cellu-
lar inclusions and neuronal loss. FTLD cases are  
classified based on the abnormal protein contents of 
the cellular inclusions: microtubule-associated pro-
tein tau, transactivation response DNA-binding pro-
tein (TDP) 43, fused in sarcoma (FUS), or proteins of 
the ubiquitin proteasome system (UPS) [1, 2]. FTLD 
is not known to be associated with conventional  
vascular risk factors [3], but recent studies on  
human tissue indicate structural and functional  
cerebrovascular alterations that may be intrinsic to 
the disease [4–10]. 

Lewy body disease (LBD) is characterised  
neuropathologically by alpha-synuclein containing 
inclusions [11, 12]. Like FTLD, LBD has not been  
associated with conventional vascular risk factors 
[13, 14], but potential mechanisms of cortical  
hypoperfusion have been described, including car-
diovascular autonomic dysfunction [15–17], intrinsic 
cholinergic denervation of blood vessels [18–20], 
impaired cortical angiogenesis [21], and reduced 
cortical capillary density [22, 23]. Information on  
histopathological signs of cerebrovascular altera-
tions in FTLD and LBD is limited. 

We have previously applied the term “rasp-
berry” to refer to a histological finding of ≥ 3 trans-
versally sectioned vascular lumen within a common 
perivascular space (Fig. 1) [24–27]. A more recently 
introduced and similarly defined term is “multi-lu-
men vascular profiles” [28]. To illustrate the link to 
our previous studies, the term “raspberry” will be 
used in the present work. There are older terms  
(including glomerular loop formations, vascular  
bundles, vascular wickerworks, and vascular convo-
lutes) that refer to several distinct vascular for-
mations which are best visualised three-dimension-
ally but lack definitions adapted for a two-dimen-
sional histological context [29–32]. Raspberries may 
constitute cross-sectional counterparts to some of 
these vascular formations, but the extent of this 
overlap has not been established. 

 

Fig. 1 A cortical microvascular raspberry, measuring 60 µm in diameter. Stain: haematoxylin-eosin. 

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In archival brain tissue from postmortem neu-
ropathological examinations, raspberries are highly 
prevalent in the neocortex, basal ganglia, hippocam-
pus, and brainstem, while occurring only rarely in 
white matter and in the cerebellum [26]. In our  
experience, raspberries are typically composed of 
arterioles and may focally constitute up to 3 %  
of the cortical blood vessels. We have previously 
demonstrated increased cortical raspberry density 
in association with vascular dementia [24], cerebral 
atherosclerosis [25, 26], and hypertensive disease 
(exploratory finding [27]), potentially indicating that 
the mechanisms of raspberry formation overlap 
with those that lead to cerebrovascular disease. 
However, an independent, positive association be-
tween raspberry density [27], or multi-lumen vascu-
lar profiles [28], and advancing age has also been  
observed, indicating that additional mechanisms 
may be involved, as ageing is associated with distinct 
effects on the vasculature [33, 34]. 

Knowledge on the distribution of raspberries 
among neurodegenerative diseases would be valua-
ble to further explore the extent to which increased 
raspberry density may occur separately from con-
ventional vascular risk factors and cerebrovascular 
disease. We have previously observed an increased 
cortical raspberry density in a small group of FTLD 
patients (n = 10) compared to control cases, but this 
finding did not achieve statistical significance [24]. 
The same study indicated a similar but weaker trend 
for patients with Alzheimer’s disease [24], while a 
later study provided no indication of an increased 
raspberry density in patients with Alzheimer pathol-
ogy [27]. No previous study has been designed to  
examine the raspberry density in LBD. An investiga-
tion including LBD would also enable stratification 
according to co-occurring Alzheimer pathology, 
which frequently accompanies this disease [35]. 

As such, the aim of the current study was to  
examine the frontocortical raspberry density in  
frontotemporal lobar degeneration (FTLD) and Lewy 
body disease (LBD) in an adequately dimensioned 
study sample, and to progress with exploratory  
subgroup analyses if supported by the primary  
statistical analysis. 

Materials and methods 

Study population 

The study population was drawn retrospec-
tively from patients who had undergone a diagnostic 
postmortem neuropathological examination at Clin-
ical Genetics, Pathology, and Molecular Diagnostics, 
Region Skane, Lund. The autopsy reports were  
accessed via the digital systems Sympathy (cases 
prior to April 2019) and LIMS RS. The medical  
records were accessed via the digital system Melior, 
in which public specialist healthcare performed in 
Region Skane is documented. All histotechnical  
procedures and diagnostic examinations had been 
performed prior to the start of the study; the details 
of the macro- and microscopic neuropathological 
examination have been described previously [36]. 

Cases with FTLD and LBD were retrieved from 
January 2001 to December 2022. The FTLD cases had 
been diagnosed according to published consensus 
recommendations, including, when applicable, as-
signment of a specific diagnosis [1, 2, 37–40]. Like-
wise, the LBD cases had been diagnosed according 
to consensus recommendations; for inclusion, the 
cases needed to be of neocortical or limbic category 
[11, 12]. The control cases were drawn from April 
2019 to December 2022 and consisted of individuals 
who were over 49 years old at death and who were 
not diagnosed with dementia according to the  
medical records. 

In all cases, the autopsy reports were as- 
sessed regarding co-occurring neuropathology. 
Brain weight and findings of atherosclerotic plaques 
in the basilar artery and circle of Willis were noted 
(referred to as cerebral atherosclerosis), as were 
findings of cerebral arteriolosclerosis [41]. Mixed 
pathology defined as more than one cerebral infarct 
resulted in exclusion. Likewise, co-occurring neuro-
degenerative disease resulted in exclusion, with the 
exception of primary age-related tauopathy or  
Alzheimer’s disease neuropathologic change with 
neurofibrillary tangle (NFT) pathology correspond-
ing to Braak stage II or lower [42–44]. In cases with 
LBD, NFT pathology up to Braak stage IV was  
accepted due to the known co-occurrence of LBD  
 
 
 

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and Alzheimer-type pathology [35]. Other forms of 
neuropathological comorbidity were noted, but did 
not result in exclusion. 

Patients included in our previous study on rasp-
berries in FTLD were deemed eligible for inclusion, 
since they were considered not to differ from the 
rest of the study sample in any systematic way [24]. 
After assessment, nine of the ten FTLD cases from 
this previous study were included (in one case, an 
adequately dimensioned glass slide was not availa-
ble; see next section). Because the raspberry density 
of these cases had been measured using an older 
method, they were re-quantified along with the 
other cases, as described in the next section. 

Raspberry quantification and assessment of cor-
tical atrophy 

The raspberry quantification was performed on 
whole slide images of scanned tissue sections in the 
same manner as in our latest study on this topic [27]. 
For each included individual, the cortical area of one 
6-µm thick haematoxylin-eosin-stained tissue sec-

tion from the frontal lobe (prepared from a forma-
lin-fixed paraffin-embedded tissue block and 
mounted on a 76 × 26 mm glass slide) was viewed in 
either Aperio ImageScope (cases prior to April 2019) 
or Sectra IDS7. The tissue section had been sampled 
from Brodmann area 10 in most cases, but tissue 
sections from other parts of the frontal lobe were 
also considered acceptable. For each tissue section, 
the number of cortical raspberries was noted, corre-
lated with the size of the examined area (median 
1.89 cm²), and reported as raspberries/cm² (Fig. 2). 
All quantification was performed blinded to patient 
characteristics. 

The degree of frontocortical atrophy was as-
sessed in well-orientated parts of the tissue samples 
and ranked on a scale from 0 to 3 (none, mild, mod-
erate, or severe) based on the overall impression of 
cortical thinning, neuropil rarefaction, and neuronal 
loss. To aid in the assessment, each slide was com-
pared to a template of representative micrographs 
(Fig. 3). All assessments were performed by a single 
examiner without access to data on raspberry  
density or other patient characteristics. 

 

 

Fig. 2 Overview of a tissue section from the frontal lobe. The cortex has been delineated, and the raspberries within the delineated area 
have been marked. Stain: haematoxylin-eosin. 

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Fig. 3 A–D Template with representative micrographs ranked as A no (0), B mild (1), C moderate (2) and D severe (3) frontocortical atrophy. 
Stain: haematoxylin-eosin. Scalebar: 200 µm. 

 

Statistics 

A sample size calculation performed in Epitools 
[45] indicated that 88 individuals per group would 
enable the detection of a mean difference in rasp-
berry density of 3 raspberries/cm² with a 95 % level 
of confidence and 80 % statistical power. When  
increasing the level of confidence to 98 % to provide 
an approximate adjustment for multiple tests (three 
tests), a group size of 112 individuals was indicated. 
As such, we aimed to include at least 88 individuals 
per group, and optimally 112 individuals per group. 

IBM SPSS Statistics Version 28 was used to per-
form the statistical analyses. The difference in mean 
raspberry density between the three groups was  
analysed using one-way Welch’s ANOVA, followed 
by the Games-Howell post hoc test due to the  
unbalanced design. When the post hoc test  
indicated a difference between any two of the 
groups, they were further analysed with two multi-
ple linear regression models wherein age, sex, and 
either brain weight or microscopic cortical atrophy 
were included as potential confounding factors.  

Exploratory subgroup analyses addressed the rasp-
berry density in relation to neurodegenerative  
disease subtype (tested with the non-parametric 
Kruskal-Wallis test), and in relation to brain weight 
and cortical atrophy (tested with Spearman rank 
correlation). A P value of ≤ 0.05 was considered  
statistically significant. 

Results 

The control group consisted of 105 individuals, 
the LBD group of 80 individuals, and the FTLD group 
of 98 individuals (the distribution of LBD and FTLD 
subtypes is shown in Fig. 4). Demographics, markers 
of brain atrophy, and neuropathological findings of 
cerebrovascular disease are reported in Table 1; 
other neuropathological findings did not occur in the 
FTLD and LBD groups, with the exception of two 
cases in the LBD group, who had been diagnosed 
with cerebral metastases. In the control group, the 
neuropathological findings were more diverse, but 
the raspberry density of control cases with neuropa-
thological comorbidity (which constituted 31 % of 
the control group) was similar to that of control 
cases with no comorbidity (Table 2). 

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Fig. 4 Neuropathological classification of the LBD and FTLD groups. Numbers in brackets indicate n. C9orf72 chromosome 9 open reading 
frame 72 gene; CBD corticobasal degeneration; FTLD frontotemporal lobar degeneration; FUS fused in sarcoma; LBD Lewy body disease; 
MAPT microtubule-associated protein tau gene; NFT neurofibrillary tangle; NOS not otherwise specified; PiD Pick’s disease; PSP progres-
sive supranuclear palsy; TDP transactivation response DNA-binding protein; UPS ubiquitin proteasome system. 

 

Table 1: Individual variables including neuropathology details 

Variable Control LBD FTLD Total 

N 105 80 98 283 

Female sex 42 (40 %) 24 (30 %) 48 (49 %) 114 (40 %) 

Median age at death (yr) 72 (50–92) 77 (51–99) 73 (44–92) 74 (44–99) 

Median brain weight (g) 1367 (875–1900) 1367 (986–1698) 1185 (610–1570) 1301 (610–1900) 

No cortical atrophy 87 (83 %) 24 (30 %) 12 (12 %) 123 (43 %) 

Mild cortical atrophy 18 (17 %) 50 (63 %) 43 (44 %) 111 (39 %) 

Moderate cortical atrophy 0 6 (8 %) 27 (28 %) 33 (12 %) 

Severe cortical atrophy 0 0 16 (16 %) 16 (6 %) 

Single cerebral infarct 24 (23 %) 13 (16 %) 15 (15 %) 52 (18 %) 

Cerebral arteriolosclerosis 29 (28 %) 18 (23 %) 32 (33 %) 79 (28 %) 

Cerebral atherosclerosis 25/87 (29 %) 21/69 (30 %) 27/87 (31 %) 73/243 (30 %) 

Table 1 Characteristics of the study sample. Numbers represent frequency unless otherwise indicated in the Variable column. Intervals 
represent min–max. For variables with incomplete data, full quotients are provided. Other neurodegenerative diseases and cases with 
multiple infarcts had been excluded from the sample as described under Study population (Materials and methods). LBD Lewy body 
disease; FTLD frontotemporal lobar degeneration. 
 

 

 

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Table 2: Neuropathological comorbidity in the con-
trol group 

Variable Frequency 
Median raspberry 
density (min–max) 

Demyelinating 
disease 

2 (2 %) 2.0 (0.8–3.2) 

Infection 17 (16 %) 3.1 (0.5–19.2) 

Malignancy 8 (4 %) 2.8 (1.2–7.8) 

Malformation 2 (2 %) 1.7 (0.8–2.6) 

Toxic disease 4 (4 %) 5.0 (3.2–9.2) 

Traumatic brain 
injury 

1 (1 %) 16.4 

Any finding* 33 (31 %) 3.1 (0.5–19.2) 

No finding* 72 (69 %) 3.9 (0–19.2) 

Total 105 (100 %) 3.3 (0–19.2) 

Table 2 Frontocortical raspberry density (raspberries/cm²) 
among control cases in relation to neuropathological comorbid-
ity. *  neuropathologically verified demyelinating disease, infec-
tion, malignancy, malformation, toxic disease, and traumatic 
brain injury. 

There was a higher raspberry density in the 
FTLD group compared to both the LBD and control 
groups, and a slightly higher raspberry density in the 
LBD group compared to the control group (Fig. 5). 
The one-way Welch’s ANOVA indicated statistically 
significant differences between the three groups 
(P < 0.001), and the Games-Howell post hoc test 
demonstrated significant differences between the 
FTLD and control groups (P < 0.001), as well as be-
tween the FTLD and LBD groups (P = 0.001). In con-
trast, the LBD and control groups did not differ at a 
statistically significant level (P = 0.69).  

When comparing the FTLD group to the LBD 
group using multiple linear regression, the differ-
ence in raspberry density remained statistically sig-
nificant when including age, sex, and either brain 
weight or microscopic cortical atrophy in the analy-
sis (Table 3). When comparing the FTLD group to the 
control group, the results remained statistically sig-
nificant when including age, sex, and brain weight in 
the analysis, while a trend towards statistical signifi-
cance was observed when instead including age, 
sex, and cortical atrophy (Table 4). 

 

Fig. 5 Raspberry density (raspberries/cm²) of the frontal cortex 
in relation to FTLD, LBD, and control cases. Lines and dots indi-
cate medians and interquartile ranges, respectively. * P = 0.001 
(Games-Howell post hoc test). ** P < 0.001 (Games-Howell post 
hoc test). FTLD frontotemporal lobar degeneration; LBD Lewy 
body disease; ns not significant. 

Table 3: Statistical comparison of raspberry density 
between the FTLD and LBD groups 

Games-Howell post hoc test* 

Independent variable P value (95 % CI) 

FTLD 0.001 (1.0;5.0) 

Multiple linear regression, model 1 

Independent variable P value (95 % CI) 

FTLD 0.034 (0.2;4.6) 

Age at death (y) 0.34 (-0.5;0.2) 

Female sex 0.85 (-2.2;1.9) 

Brain weight (g) 0.02 (-0.1;-0.001) 

Multiple linear regression, model 2 

Independent variable P value (95 % CI) 

FTLD 0.012 (0.6;4.5) 

Age at death (y) 0.069 (-0.007;0.2) 

Female sex 0.68 (-1.4;2.1) 

Cortical atrophy (0–3) 0.02 (0.2;2.4) 

Table 3 P values with 95 % CI from the Games-Howell post hoc 
test and multiple linear regression models aimed at comparing 
the FTLD group (n = 98) to the LBD group (n = 80). Statistically 
significant results have been marked in bold. Outcome variable: 
frontocortical raspberry density (raspberries/cm²). *The post 
hoc test was preceded by one-way Welch ANOVA which in-
cluded all three groups (n = 283) and achieved statistical signifi-
cance (P < 0.001). CI confidence interval; LBD Lewy body dis-
ease; FTLD frontotemporal lobar degeneration. 

 

 

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Table 4: Statistical comparison of raspberry density 
between the FTLD and control groups 

Games-Howell post hoc test* 

Independent variable P value (95 % CI) 

FTLD < 0.001 (1.7;5.5) 

Multiple linear regression, model 1 

Independent variable P value (95 % CI) 

FTLD 0.004 (1.0;5.0) 

Age at death (y) 0.072 (-0.007;0.2) 

Female sex 0.93 (-1.8;2.0) 

Brain weight (g) 0.38 (-0.008;0.003) 

Multiple linear regression, model 2 

Independent variable P value (95 % CI) 

FTLD 0.054 (-0.04;4.1) 

Age at death (y) 0.014 (0.02;0.2) 

Female sex 0.88 (-1.4;1.7) 

Cortical atrophy (0–3) 0.061 (-0.05;2.2) 

Table 4 P values with 95 % CI from the Games-Howell post hoc 
test and multiple linear regression models aimed at comparing 
the FTLD group (n = 98) to the control group (n = 105). Statisti-
cally significant results have been marked in bold. Outcome var-
iable: frontocortical raspberry density (raspberries/cm²). *The 
post hoc test was preceded by one-way Welch ANOVA which 
included all three groups (n = 283) and achieved statistical sig-
nificance (P < 0.001). CI confidence interval; FTLD frontotem-
poral lobar degeneration. 

Given the results of the primary statistical  
analysis, further analyses were undertaken to  
explore the variation in raspberry density within the 
FLTD group. These demonstrated a trend towards a 
positive correlation between raspberry density and 
microscopic cortical atrophy (P = 0.062; rho = 0.19; 
Fig. 6, A), and a corresponding trend towards a  
negative correlation between raspberry density and 
brain weight (P = 0.078; rho = -0.19; Fig. 7, A). The 
most frequent diagnosis among FTLD cases with no 
cortical atrophy was progressive supranuclear palsy, 
whereas most cases with severe cortical atrophy 
were diagnosed with FTLD-TDP (various types). As 
expected, cortical atrophy correlated negatively 
with brain weight (P < 0.001; rho = -0.55). 

Non-parametric testing (Kruskal-Wallis) was in-
conclusive when analysing the raspberry density in 
FTLD in relation to proteinopathy (P = 0.46) and  
specific diagnosis; the latter comparisons were  
restricted to FTLD-tau (P = 0.28) and -TDP (P = 0.52; 
Fig. 7, B–D). These analyses remained inconclusive 
also after excluding small groups (n < 5; not shown). 
For descriptive data on the raspberry density in LBD 
in relation to limbic / neocortical category and pre-
sence / absence of Braak stage III–IV NFT pathology, 
see Fig. 8, A–B. 

 

Fig. 6 A–C Raspberry density (raspberries/cm²) of the frontal cortex in relation to microscopic cortical atrophy in A FTLD (P = 0.062; 
rho = 0.19; Spearman rank correlation), B LBD (not statistically analysed) and C control cases (not statistically analysed). Lines indicate 
medians; numbers in brackets indicate n. FTLD frontotemporal lobar degeneration; LBD Lewy body disease. 

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Fig. 7 A–D Raspberry density (raspberries/cm²) of the frontal cortex in FTLD in relation to A brain weight (P = 0.078; rho = -0.19; Spearman 
rank correlation), B proteinopathy (P = 0.46; Kruskal-Wallis test), C FTLD-tau (P = 0.28; Kruskal-Wallis test), and D FTLD-TDP (P = 0.52; 
Kruskal-Wallis test). Lines indicate medians; numbers in brackets indicate n. The statistical analyses of raspberry density in relation to  
B–D remained inconclusive also after excluding small groups (n < 5; not shown). CBD corticobasal degeneration; FTLD frontotemporal 
lobar degeneration; FUS fused in sarcoma; NOS not otherwise specified; PiD Pick’s disease; PSP progressive supranuclear palsy; TDP-43 
transactivation response DNA-binding protein 43, UPS ubiquitin proteasome system. 

 

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Fig. 8 A–B Raspberry density (raspberries/cm²) of the frontal cortex in LBD in relation to A LBD category (not statistically analysed), and B 
co-occurring NFT pathology (not statistically analysed). Lines indicate medians; numbers in brackets indicate n. LBD Lewy body disease; 
NFT neurofibrillary tangle. 

 

Discussion 

The current study examined the raspberry  
density of the frontal cortex in FTLD, LBD and control 
cases, and found it to be increased in FTLD  
compared to both of the other groups. The results 
did not indicate any difference between the LBD and 
control groups. Based on our sample size calcula-
tion, the FTLD (n = 98) and control groups (n = 105) 
were considered sufficiently large, but the compari-
sons involving the LBD group (n = 80) were at risk of 
being underpowered. Low power could reduce the 
chances of detecting true differences, while also  
increasing the risk of overestimating effect sizes. 
With this limitation in mind, our results provide no 
indication of a relevant difference in frontocortical 
raspberry density between LBD and control cases. 

According to our multiple linear regression 
analysis, the increased raspberry density in FTLD  
relative to the LBD group was independent of varia-
tions in age, sex, brain weight, and microscopic  
cortical atrophy. The difference in raspberry density 

between the FTLD and control groups was statisti-
cally significant when including age, sex, and brain 
weight in the analysis, but not when exchanging 
brain weight for cortical atrophy (P = 0.054). It 
should be noted that most FTLD and LBD cases  
exhibited some degree of cortical atrophy, whereas 
most control cases did not. As such, it is possible that 
a larger study sample – wherein more FTLD and  
control cases would exhibit the same degree of  
cortical atrophy – could have achieved statistical  
significance. 

However, we also observed a trend towards a  
positive correlation between raspberry density and 
cortical atrophy in the FTLD group (P = 0.062), which 
is similar to the finding of an increasing endothelial 
cell proportion with increasing cortical atrophy  
described in a recent study on FTLD-TDP [9]. In one 
respect, our finding could indicate that the  
increased raspberry density in FTLD is at least  
partially secondary to cortical atrophy. Our previous 
studies on raspberries have not indicated an associ-
ation between raspberry density and brain atrophy 

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[26, 27], but such an association could still exist 
within the FTLD population (or in a broader context 
of neurodegeneration, as potentially indicated by 
the multiple linear regression models). Cortical  
atrophy could appear to increase the raspberry  
density by reducing the distance between blood  
vessels while the absolute number of vessels re-
mains constant. Alternatively, neuropil rarefaction 
could reduce the stability around cortical arterioles 
and lower the threshold for arteriolar buckling and 
stretching with ensuing elongation [46], possibly  
resulting in crowding of multiple arteriolar branches 
within the same perivascular space. 

However, the trend towards a positive correla-
tion between raspberry density and cortical atrophy 
could also be due to the FTLD disease process  
causing both cortical atrophy and raspberry for-
mation. Notably, vascular alterations have been de-
scribed in experimental studies on the pathomecha-
nisms of tau and TDP-43 [47–52], in autopsy studies 
on FTLD [4–10], and in amyotrophic lateral sclerosis 
[53], an entity that overlaps clinically, pathologically, 
and genetically with FTLD-TDP [54]. These altera-
tions include abnormal remodelling of the extracel-
lular matrix [8–10, 48, 51, 52], increased angiogene-
sis [8–10, 48, 51], altered microvascular density and 
morphology [6, 8, 48], compromised blood brain 
barrier integrity [5, 8, 47, 50, 52], and abnormal 
blood flow [48, 49]. Among these mechanisms,  
remodelling of the vascular wall extracellular matrix 
could alter the stiffness of cortical arterioles and 
lower the threshold for arteriolar buckling [46], in 
addition to the possible effects of neuropil rarefac-
tion discussed above. Alternatively, the increased 
raspberry density in FTLD could be a manifestation 
of abnormal angiogenesis and arterialisation, as  
previously hypothesised due to the increased rasp-
berry density in vascular dementia [24]. 

Our exploratory analyses of the raspberry den-
sity in FTLD in relation to proteinopathy and specific 
diagnosis were inconclusive. Looking at the descrip-
tive data, the raspberry density in FTLD-TDP was 
slightly higher than in FTLD-tau, but the FTLD-TDP 
group also exhibited more severe cortical atrophy. 
Among the FTLD-tau and -TDP subgroups, the high-
est raspberry density was found in FTLD-TDP type B. 
Among the eight patients with a documented 
C9orf72 mutation, six manifested as FTLD-TDP type 

B (one of these cases also had tau pathology), and 
the other two as type A. As a group, these eight  
patients exhibited a notably high raspberry density 
(median 11.6 raspberries/cm², compared to 7.1 
raspberries/cm² for the entire FTLD group). Due to 
the low number of known C9orf72 mutation carriers 
and large proportion of individuals with unknown 
genetic status in our study population, the relevance 
of this observation is unclear. Interestingly, individ-
uals with a C9orf72 mutation exhibit a presympto-
matic decline in cerebral blood flow that may be less 
dependent on brain atrophy compared to GRN and 
MAPT mutation carriers [55], and a recent experi-
mental study indicated that endothelial cells derived 
from C9orf72 mutation carriers have an abnormal 
phenotype that potentially affects the substrate  
exchange with neurons (other dysfunctional fea-
tures were also reported [56]). 

Our results do not indicate an increased  
frontocortical raspberry density in LBD compared to 
control cases. It is possible that the pathomecha-
nisms of LBD simply do not induce raspberry  
formation. Alternatively, raspberry formation could 
be partially inhibited by anti-angiogenic effects of  
alpha-synuclein accumulation [21]. It should be 
noted that hypoperfusion of the occipital lobes is 
considered characteristic of LBD [57]; however, the 
hypoperfusion in LBD is often more widespread and 
involve also the frontal lobes [58, 59]. As such, we 
would have expected to detect an increased fronto-
cortical raspberry density in the LBD group if an  
association between increased raspberry density 
and LBD were to exist, but an examination of the  
occipital raspberry density in LBD could be valuable 
to further explore this relationship. 

The main limitations of this study are the retro-
spective design and the semiquantitative assess-
ment of cortical atrophy. Because all autopsies were 
initiated based on clinical indications, relatively  
lenient exclusion criteria were deemed necessary to 
acquire a sufficiently large study sample. Conse-
quently, a proportion of the control cases exhibited 
neuropathological comorbidity that could affect the 
external validity, although importantly, the rasp-
berry density of cases with neuropathological 
comorbidity was similar to that of cases with no such 
findings (with the exception of the single case with 
traumatic brain injury; Table 2). Ordinal ranking of 

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cortical atrophy was considered less dependent on 
sample orientation than measuring cortical thick-
ness. With this semiquantitative approach, a differ-
ence in raspberry density beyond what may be  
explained by cortical atrophy was indicated, but the 
comparison between FTLD and control cases was 
statistically inconclusive, and our results also  
indicated a potential correlation between raspberry 
density and cortical atrophy. As such, an assessment 
of the raspberry density in FTLD in relation to a 
quantitative measure of cortical atrophy is moti-
vated to validate the results. 

With these limitations in mind, the study adds 
to previous findings of increased raspberry density 
in relation to advancing age and vascular dementia, 
potentially indicating that various underlying causes 
may converge in increased raspberry formation. The 
study does not enable conclusions on whether the 
raspberry density is higher within a certain part of 
the FTLD spectrum. However, given the lack of asso-
ciation between raspberry density and LBD, altered 
raspberry density may not be a general feature of 
neurodegenerative disease. Future studies are 
needed to determine whether increased raspberry 
density in FTLD could function as a marker for more 
widespread vascular alterations, by examining the 
raspberry density in FTLD in relation to overall  
vascular density, protein aggregates in the vascular 
wall, signs of compromised blood brain barrier, or 

altered extracellular matrix deposition. An examina-
tion of the raspberry density in other conditions that 
manifest with tau or TDP43 pathology may also be 
motivated. 

Declarations 

Ethics statement 

The study was approved by the Swedish Ethical 
Review Authority, application number 2019-00080 
and amendments number 2021-05753-02 and 2023-
03097-02. 

Conflicts of interest statement 

The authors declare no conflicts of interest. 

Funding statement 

The study was supported by Lund University, 
Region Skane, and the Trolle-Wachtmeister Founda-
tion for Medical Research. 

Acknowledgements 

The authors extend their gratitude to the staff 
at Clinical Genetics, Pathology, and Molecular Diag-
nostics, Region Skane, Lund, for invaluable technical 
assistance throughout the project. 

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	Original Paper
	Abbreviations
	Introduction
	Materials and methods
	Study population
	Raspberry quantification and assessment of cortical atrophy
	Statistics

	Results
	Discussion
	Declarations
	Ethics statement
	Conflicts of interest statement
	Funding statement
	Acknowledgements

	References

