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Advanced Neurology Neuroimaging regarding spatial navigation in AD

than episodic memory in identifying progressors. It has in the hippocampus in APP/PS1 mice were observed. The
been emphasized by the researchers that future work discrepant results of the associations between Aβ deposits
should incorporate neuroimaging and biomarker data to and spatial navigation in animal studies may be partly due
assess whether baseline spatial navigation was related to to the various extent of extrahippocampal pathology and
longitudinal alterations in brain structure, function, and different mechanisms that underlie neuronal dysfunction
AD biomarkers. and spatial navigation impairment at different stages of
In summary, although spatial navigation was less Aβ pathology [115] . After healthy older adults completed an
investigated in the preclinical AD stage, emerging data on-road driving test, the Santa Barbara Sense of Direction
have suggested that SCD subjects, risk gene carriers, scale, and the Driving Habits Questionnaire, Allison et al.
and elderly individuals with abnormal AD biomarkers found that CSF Aβ , but not Tau or pTau , was associated
42
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experience difficulties in spatial navigation compared with self-reported navigation abilities, which further
to the navigation ability of NCs. Decreased functional mediated the relationships between CSF Aβ and driving
42
connectivity measured by rs-fMRI may indicate disruption range. These findings indicated that brain Aβ deposition
of navigation networks in subjects with incipient AD. could contribute to patients’ reduced ability to perceive
the environment to navigate, which consequently results
4. Spatial navigation impairment and in older adults with AD pathology having a limited drive
related pathophysiological changes range [116] .
Interestingly, other studies have focused on the
4.1. Spatial navigation impairment and AD relationships between Tau hyperphosphorylation and
pathology of Aβ and Tau
spatial navigation impairments. Using a transgenic mouse
It has been widely recognized that the typical pathological model, Fu et al. demonstrated that the accumulation of
changes in AD are extracellular Aβ deposition and Tau pathology in the entorhinal cortex was associated with
the formation of neurofibrillary tangles caused by Tau excitatory neuron loss, grid-cell dysfunction, and deficits
hyperphosphorylation. The entorhinal cortex is one in spatial learning and memory [117] . This was the first study
of the brain regions first involved in phosphorylated that showed a relationship between Tau pathology and
Tau (pTau) [7,112] . Multimodal information from cortices grid cell dysfunction in vivo, which may further provide
converges in the hippocampus primarily through the a link between Tau pathology and spatial navigation
entorhinal cortex, with the medial part encoding and impairments in patients with early AD. Notably, the pattern
transferring spatial information [113] . However, the in pTau staining across the parietal-hippocampus network
relationships between spatial navigation impairments and is a powerful predictor of spatial learning and memory
pathological biomarkers of AD in humans have not been performance. Stimmell et al. demonstrated that female
clearly illustrated, as most studies have been conducted on mice at 6 months of age had a Tau pathological pattern
animals. identified by independent component analysis in the
Several studies have been conducted to explore the parietal-hippocampus network, with a higher density of
relationships between Aβ deposits and spatial navigation. pTau-positive cells predicting poorer spatial learning and
A study of APP/PS1 mice found that Y-maze performance memory performance in female 3xTg-AD mice [118] . This
worsened before the formation of Aβ deposits; however, indicated that spatial disorientation may be attributed to the
despite the increased Aβ load in the hippocampus and early accumulation of pTau in the parietal-hippocampus
cortex, these mice did not show impairment in spatial network in AD. Stancu et al. crossed APP/PS1 mice with 5
navigation at 6 or 9 months. This suggested that Aβ early-onset familial AD mutation (5xFAD) and TauP301S
deposition alone was not sufficient to cause strong spatial (PS19) transgenic mice and found that Tau pathology
memory impairment in mice of this mixed background was invariably and robustly aggravated in hippocampal
[119]
ancestry and age [114] . In contrast, a study by Puoliväli et al. and cortical brain regions . Most importantly, the mice
showed that total hippocampal Aβ levels in transgenic mice displayed more severe deficits in the spatial navigation task
were associated with spatial navigation impairments [115] . than the controls.
The APP/PS1 mice were impaired in water maze acquisition From the above studies, we summarize that spatial
and retention only at the age of 11–12 months. Moreover, navigation impairment may be caused by the deposition of
the levels of total Aβ 1-42 in the hippocampus were negatively Tau and/or Aβ in the entorhinal cortex, hippocampus, and
correlated with the retention score in mice in the impaired parietal cortex. More clinical studies are urgently needed
older age group. This was the first study in which significant to determine the exact relationships between spatial
correlations between age-dependent impairment of navigation impairments and pathological biomarkers of
memory retention in a traditional water maze and total Aβ AD in humans.

Volume 1 Issue 2 (2022) 7 https://doi.org/10.36922/an.v1i2.145