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Saccade abnormalities in autopsy-confirmed frontotemporal lobar degeneration and Alzheimer disease.

ABSTRACT: Deficits in the generation and control of saccades have been described in clinically defined frontotemporal dementia (FTD) and Alzheimer disease (AD).To determine the saccade abnormalities associated with autopsy-defined cases of frontotemporal lobar degeneration (FTLD) and of AD, because clinical FTD syndromes can correspond to a number of different underlying neuropathologic FTD and non-FTD diagnoses.An infrared eye tracker was used to record visually guided saccades to 10° targets and antisaccades in subjects with autopsy-confirmed FTD and subjects with autopsy-confirmed AD, a mean (SE) of 35.6 (10.0) months prior to death, and age-matched normal controls. Twelve subjects with FTD had an FTLD-TAR DNA-binding protein 43 pathology, 15 had an FTLD-tau pathology, and 1 subject showed an FTLD-fused in sarcoma protein pathology. Receiver operating curve statistics were used to determine the diagnostic value of the oculomotor variables. Neuroanatomical correlates of oculomotor abnormalities were investigated using voxel-based morphometry.Memory and Aging Center, Department of Neurology, University of California, San Francisco.A total of 28 subjects with autopsy-confirmed FTD, 10 subjects with autopsy-confirmed AD, and 27 age-matched normal controls.All subjects with FTD or AD were impaired relative to normal controls on the antisaccade task. However, only FTLD-tau and AD cases displayed reflexive visually guided saccade abnormalities. The AD cases displayed prominent increases in horizontal saccade latency that differentiated them from the FTD cases. Impairments in velocity and gain were most severe in individuals with progressive supranuclear palsy but were also present in other tauopathies. By using vertical and horizontal saccade velocity and gain as our measures, we were able to differentiate patients with progressive supranuclear palsy from other patients. Vertical saccade velocity was strongly correlated with dorsal midbrain volume.Decreased visually guided saccade velocity and gain are suggestive of underlying tau pathology in FTD, with vertical saccade abnormalities most diagnostic of progressive supranuclear palsy.

SUBMITTER: Boxer AL

PROVIDER: S-EPMC3423186 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Saccade abnormalities in autopsy-confirmed frontotemporal lobar degeneration and Alzheimer disease.

Boxer Adam L AL Garbutt Siobhan S Seeley William W WW Jafari Aria A Heuer Hilary W HW Mirsky Jacob J Hellmuth Joanna J Trojanowski John Q JQ Huang Erik E DeArmond Steven S Neuhaus John J Miller Bruce L BL

Archives of neurology 20120401 4

<h4>Background</h4>Deficits in the generation and control of saccades have been described in clinically defined frontotemporal dementia (FTD) and Alzheimer disease (AD).<h4>Objective</h4>To determine the saccade abnormalities associated with autopsy-defined cases of frontotemporal lobar degeneration (FTLD) and of AD, because clinical FTD syndromes can correspond to a number of different underlying neuropathologic FTD and non-FTD diagnoses.<h4>Design</h4>An infrared eye tracker was used to record ...[more]

PMID: 22491196

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Project description:BackgroundWe aimed to systematically describe the burden and distribution of white matter hyperintensities (WMH) and investigate correlations with neuropsychiatric symptoms in pathologically proven Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD).MethodsAutopsy-confirmed cases were identified from the Sunnybrook Dementia Study, including 15 cases of AD and 58 cases of FTLD (22 FTLD-TDP cases; 10 FTLD-Tau [Pick's] cases; 11 FTLD-Tau Corticobasal Degeneration cases; and 15 FTLD-Tau Progressive Supranuclear Palsy cases). Healthy matched controls (n = 35) were included for comparison purposes. Data analyses included ANCOVA to compare the burden of WMH on antemortem brain MRI between groups, adjusted linear regression models to identify associations between WMH burden and neuropsychiatric symptoms, and image-guided pathology review of selected areas of WMH from each pathologic group.ResultsBurden and regional distribution of WMH differed significantly between neuropathological groups (F5,77 = 2.67, P' = 0.029), with the FTLD-TDP group having the highest mean volume globally (8032 ± 8889 mm3) and in frontal regions (4897 ± 6163 mm3). The AD group had the highest mean volume in occipital regions (468 ± 420 mm3). Total score on the Neuropsychiatric Inventory correlated with bilateral frontal WMH volume (β = 0.330, P = 0.006), depression correlated with bilateral occipital WMH volume (β = 0.401, P < 0.001), and apathy correlated with bilateral frontal WMH volume (β = 0.311, P = 0.009), all corrected for the false discovery rate. Image-guided neuropathological assessment of selected cases with the highest burden of WMH in each pathologic group revealed presence of severe gliosis, myelin pallor, and axonal loss, but with no distinguishing features indicative of the underlying proteinopathy.ConclusionsThese findings suggest that WMH are associated with neuropsychiatric manifestations in AD and FTLD and that WMH burden and regional distribution in neurodegenerative disorders differ according to the underlying neuropathological processes.

Project description:Frontotemporal lobar degeneration with ? pathology (FTLD-tau) is one of a group of neurodegenerative diseases that manifests with cognitive decline. Alzheimer (AD) and cerebrovascular lesions are commonly noted in the brains of most elderly individuals, begging the question as to whether (a) coexisting AD and vascular pathology or age contribute to the development of FTLD-tau disorders and vice versa and (b) FTLD-tau-like pathology can be found in non-diseased individuals. We studied brains of FTLD-tau cases exhibiting (a) argyrophilc grain disease (AGD), (b) progressive supranuclear palsy (PSP), (c) corticobasal degeneration (CBD), or (d) Pick's disease (PiD) for coexisting AD and vascular pathology for comparison with that of non-diseased individuals and AD patients. We confirmed that AGD lowered the threshold for AD pathology to cause dementia. Such an effect was not seen in PSP, CBD, or PiD. In PiD, white matter degeneration and demyelination was observed in the frontal and temporal lobes in association with small vessel disease (SVD)-related changes in white matter arteries. Age at death varied among the four types of FTLD-tau. PiD cases were youngest at death followed by CBD, PSP, and finally AGD. In 9.8% of non-diseased controls, we found grains, coiled bodies, and/or ?-positive astrocytes mimicking an AGD-like pattern. Moreover, the prevalence of FTLD-tau pathology in non-diseased individuals increased with age. In summary, this study demonstrates that age impacts of the diversity of neuropathological changes in FTLD-tau. The age-related coexistence of AD-related pathology is, thereby, associated with AGD but not with PSP, CBD, and PiD. Moreover, severe SVD and white matter demyelination is associated with PiD indicating a role of vascular copathology in this type of FTLD-tau. Finally, our finding that FTLD-tau-related pathological lesions occur in non-diseased individuals suggests that preclinical stages of FTLD-tau exist. As such, our results indicate that age, together with vascular and AD-related copathology, contributes to the morphological appearance of FTLD-tau.

Dataset Information

Saccade abnormalities in autopsy-confirmed frontotemporal lobar degeneration and Alzheimer disease.

Publications

Saccade abnormalities in autopsy-confirmed frontotemporal lobar degeneration and Alzheimer disease.

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