Spinocerebellar ataxias (SCA) are rare neurodegenerative diseases affecting the cerebellum and its connections, leading to progressive motor disability and cognitive impairment as part of the cerebellar cognitive affective syndrome. Spatial navigation, cognitive function important for everyday movement, relies on spatial perspective taking-the ability to imagine the environment from different viewpoints. While animal and neuroimaging studies suggest a crucial role of the cerebellum in spatial navigation, research on patients with cerebellar disorders is lacking. This study aimed to investigate perspective taking in patients with SCA and Friedreich ataxia (FRDA) using two tests. The Perspective-Taking/Spatial Orientation Test (PTSOT) was administered to 30 SCA patients, 30 FRDA patients, and 34 healthy controls (HC). In addition, SCA and HC completed the Directional-approach Task and a comprehensive neuropsychological assessment. SCA patients performed significantly worse than HC on both perspective taking tests. FRDA patients performed better than SCA and differed from HC only in a subset of PTSOT measures. Perspective taking performance in SCA was associated with global cognition and multiple cognitive domains but not with cerebellar motor impairment. These findings are of potential clinical relevance, as spatial navigation deficits are known to negatively affect the mobility and independence of the affected individuals. Our findings expand the understanding of cognitive impairments in cerebellar diseases, adding spatial navigation to the spectrum of the cerebellar cognitive affective syndrome.

• Keywords
• Cerebellum, Cognition, Friedreich ataxia, Spatial navigation, Spatial perspective taking, Spinocerebellar ataxia,
• MeSH
• Adult MeSH
• Friedreich Ataxia * physiopathology   psychology   MeSH
• Cognition MeSH
• Cognitive Dysfunction physiopathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Cerebellum physiopathology   MeSH
• Neuropsychological Tests MeSH
• Spatial Navigation * physiology   MeSH
• Spinocerebellar Ataxias * physiopathology   psychology   MeSH
• Case-Control Studies MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Spatial navigation deficits are early symptoms of Alzheimer's disease (AD). The apolipoprotein E (APOE) ε4 allele is the most important genetic risk factor for AD. This study investigated effects of APOE genotype on spatial navigation in biomarker-defined individuals with amnestic mild cognitive impairment (aMCI) and associations of AD biomarkers and atrophy of AD-related brain regions with spatial navigation. METHODS: 107 participants, cognitively normal older adults (CN, n = 48) and aMCI individuals stratified into AD aMCI (n = 28) and non-AD aMCI (n = 31) groups, underwent cognitive assessment, brain MRI, and spatial navigation assessment using the Virtual Supermarket Test with egocentric and allocentric tasks and a self-report questionnaire. Cerebrospinal fluid (CSF) biomarkers (amyloid-β1-42, phosphorylated tau181 and total tau) and amyloid PET imaging were assessed in aMCI participants. RESULTS: AD aMCI participants had the highest prevalence of APOE ε4 carriers and worst allocentric navigation. CSF levels of AD biomarkers and atrophy in AD-related brain regions were associated with worse allocentric navigation. Between-group differences in spatial navigation and associations with AD biomarkers and regional brain atrophy were not influenced by APOE genotype. Self-reported navigation ability was similar across groups and unrelated to spatial navigation performance. CONCLUSIONS: These findings suggest that allocentric navigation deficits in aMCI individuals are predominantly driven by AD pathology, independent of APOE genotype. This highlights the role of AD pathology as measured by biomarkers, rather than genetic status, as a major factor in navigational impairment in aMCI, and emphasizes the assessment of spatial navigation as a valuable tool for early detection of AD.

• Keywords
• Allocentric navigation, Amyloid-β, Egocentric navigation, Entorhinal cortex, Hippocampus, Tau protein,
• MeSH
• Alzheimer Disease * genetics   cerebrospinal fluid   diagnostic imaging   complications   physiopathology   pathology   MeSH
• Amyloid beta-Peptides cerebrospinal fluid   MeSH
• Apolipoprotein E4 * genetics   MeSH
• Apolipoproteins E * genetics   MeSH
• Atrophy MeSH
• Biomarkers cerebrospinal fluid   MeSH
• Genotype MeSH
• Cognitive Dysfunction * genetics   cerebrospinal fluid   diagnostic imaging   physiopathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Magnetic Resonance Imaging MeSH
• Brain pathology   diagnostic imaging   MeSH
• Neuropsychological Tests MeSH
• Peptide Fragments cerebrospinal fluid   MeSH
• Positron-Emission Tomography MeSH
• Spatial Navigation * physiology   MeSH
• tau Proteins cerebrospinal fluid   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• amyloid beta-protein (1-42) MeSH Browser
• Amyloid beta-Peptides MeSH
• Apolipoprotein E4 * MeSH
• Apolipoproteins E * MeSH
• Biomarkers MeSH
• Peptide Fragments MeSH
• tau Proteins MeSH

Impaired spatial navigation is early marker of Alzheimer's disease (AD). We examined ability of self- and informant-reported navigation questionnaires to discriminate between clinically and biomarker-defined participants, and associations of questionnaires with navigation performance, regional brain atrophy, AD biomarkers, and biomarker status. 262 participants (cognitively normal, with subjective cognitive decline, amnestic mild cognitive impairment [aMCI], and mild dementia) and their informants completed three navigation questionnaires. Navigation performance, magnetic resonance imaging volume/thickness of AD-related brain regions, and AD biomarkers were measured. Informant-reported questionnaires distinguished between cognitively normal and impaired participants, and amyloid-β positive and negative aMCI. Lower scores were associated with worse navigation performance, greater atrophy in AD-related brain regions, and amyloid-β status. Self-reported questionnaire scores did not distinguish between the groups and were weakly associated with navigation performance. Other associations were not significant. Informant-reported navigation questionnaires may be a screening tool for early AD reflecting atrophy of AD-related brain regions and AD pathology.

• Keywords
• Clinical neuroscience, Disease, Neuroscience,
• Publication type
• Journal Article MeSH