Results All neuropathologies were associated with clinical
dementia when controlling for cortical plaques and tangles except
Hirano bodies, GVD and brainstem plaques. These included:
hippocampal and entorhinal gliosis; cortical, hippocampal and
entorhinal neuronal loss, along with brainstem neuronal loss,
gliosis, pigmentary incontinence, Lewy bodies and tangles. See
Figure 2. Pick bodies were present in five individuals, all had
clinical dementia. Less common and disregarded pathologies in late
onset dementia: what are we missing? Hannah A.D. Keage 1,2, Paul G.
Ince 3, Fiona E. Matthews 4, Stephen B Wharton 3, Ian McKeith 5 and
Carol Brayne 2 1 Cognitive Neuroscience Laboratory, School of
Psychology and Social Work, University of South Australia,
Australia; 2 Department of Public Health and Primary Care,
University of Cambridge, UK; 3 School of Medical and Biomedical
Sciences, University of Sheffield, UK; 4 MRC Biostatistics Unit,
Cambridge, UK; 5 Newcastle Biomedicine, University of Newcastle, UK
Contact Dr Hannah Keage [email protected] Supported by a
Marie Curie International Incoming Fellowship and an Australian
NHMRC Training Fellowship Background o The pathological basis of
late onset dementia is typically conceptualised in terms of
cortical amyloid, tau and vascular pathologies. o The significance
of less common pathologies associated with dementias such as Pick
bodies, cortical atrophy and subcortical tau to dementia in the old
is unknown. o The independent contributions of neuropathologies
generally accepted to be common in dementia such as Hirano bodies,
gliosis, granulovacuolar degeneration (GVD) are also unknown. o The
current study investigated the relationship between these less
common and disregarded neuropathologies to late onset dementia in a
population-based sample of older people. Method o The sample was
drawn from the Epidemiological CLInicoPathological Studies in
Europe (EClipSE) project (www.eclipsestudy.eu) which is a
harmonisation of population-based autopsy and clinical data (in
this case, the MRC Cognitive Function and Ageing Study and the City
of Cambridge over-75 Cohort). o 627 individuals aged 71-103 years,
55% clinically demented at death. o Pathologies assessed included:
Pick bodies, severe neuronal loss, gliosis and GVD in the cortex
and/or hippocampus, as well as brainstem plaques, tangles, severe
neuronal loss, gliosis, pigmentary incontinence and Lewy bodies.
See Figure 1 for selected examples. o Brainstem regions included:
substantia nigra, nucleus basalis, raphe nucleus, locus coeruleus
and vagas nerve. o Associations between each pathological marker
and clinical dementia were assessed, taking into account cortical
plaques and tangles. Key points o The underlying neuropathological
basis of late onset dementia is complex. o The brainstem may play a
more critical role than previously recognised. Conclusion Findings
contribute to the emerging understanding that late onset dementia
is associated with a broad range of neuropathologies and anatomical
regions. Gliosis and neuronal loss appear to play independent roles
(when taking into account classic makers), as do a variety of
pathologies within the brainstem. The population-based approach
gives extra weight to results as individuals were sourced from, and
the sample is representative of, the general population rather than
people referred to clinics or brain banks. Future work should
include these less common and disregarded pathologies and
anatomical regions. Figure 1. Left The CA1 region of the
hippocampus showing a Hirano body (open arrow) and granulovacuolar
degeneration in 2 neurons. Scale bar 0.05mm. Middle entorhinal
cortex showing neuronal loss and superficial gliosis. Scale bar
0.5mm. Right atrophic cerebral cortex showing neuronal loss and
gliosis in a case showing Frontotemporal dementia ubiquitin
positive pathology. Scale bar 1mm. Figure 2. Associations (odds
ratios and 95% confidence internals) between cortical, hippocampal
and entorhinal, and brainstem pathologies and clinical dementia
status at death. Model 1/M1adjusted for age group, study and sex
Model 2/M2adjusted for age group, study, sex, cortical neuritic
plaques and Braak stage Risk of clinical dementia: cortical,
hippocampal and entorhinal pathologies Risk of clinical dementia:
brainstem pathologies Odds ratio Key Ent.cotex entorhinal cortex
Hip. hippocampus Pig.incontinence - pigmentary incontinence GVD
granulovacuolar degeneration Hirano Hirano bodies