Dementia and neurodevelopmental predisposition: Cognitive dysfunction in presymptomatic subjects precedes dementia by decades in frontotemporal dementia

Abstract

Dementia is typically thought of as a disease caused by the process of aging. Few studies have addressed the premorbid neuropsychological alterations in subjects at risk for the disease--an issue of great importance for the understanding and treatment of degenerative dementias. We used knowledge of the mutation carrier status in a family with inherited dementia to address this issue more efficiently than is possible in the general population, or in cases of inherited dementia where the mutational basis is unknown. Standard neuropsychological tests were used to detect evidence of dysfunction in frontal executive systems in 10 presymptomatic subjects with known mutation carrier status in the highly penetrant condition, frontotemporal dementia and parkinsonism linked to chromosome 17. Presymptomatic carriers demonstrated cognitive dysfunction that was not present in 6 nonmutation-carrying relatives. Strikingly, frontal-executive dysfunction was apparent in some of the youngest mutation carriers many decades prior to the predicted onset of dementia. Thus, this dysfunction may reflect the native cognitive capacities of affected subjects. These results suggest a potentially important neurodevelopmental component to a dementing condition that has been predominantly considered to be a disease of aging; accordingly, this issue warrants study in other families to assess the applicability of these findings.

Socioeconomic status moderates the association between carotid intima-media thickness and cognition in midlife: Evidence from the Whitehall II study

“…12,23 While the mechanisms underlying this association remain to be explicated, it is plausible that progressive occlusion of arteries in vascular disease is likely to include occlusion of the cerebral arteries resulting in cerebral tissue loss and cognitive decline. Evidence of the link between impaired cognitive function in middle age and subsequent dementia, 8,10,11 leads us to believe that the results reported here are clinically relevant. Thus, attempts to use vascular risk profiles to predict latelife dementia in people of middle age 45 ought to consider the fact that a certain risk profile might have a different meaning in different SES groups.…”

“…This association has also been explored in middle aged subjects as research suggests that the sub-clinical phase of reduced cognitive function precedes the appearance of diagnosed dementia. [8][9][10][11] Common carotid artery intima media thickness (IMT) is one of the more recently identified vascular risk factors. 2,12 It is a marker of structural and functional vessel wall properties and is seen as an early indicator of generalized atherosclerosis, 13 or the extent of sub-clinical atherosclerosis.…”

Granulin mutation drives brain damage and reorganization from preclinical to symptomatic FTLD

“…Conversely, in preclinical carriers of MAPT mutation, deficits in language and executive function were detectable even 20 years before clinical onset (Geschwind et al, 2001). A possible explanation for these observations is that, in PGRN presymptomatic subjects, normal cognition is maintained by the compensatory mechanism of increased connectivity within the SN.…”

Progranulin Deficiency Decreases Gross Neural Connectivity But Enhances Transmission at Individual Synapses

“…Indeed, comparisons of family members with and without pathogenic mutations leading to FTD demonstrate that presymptomatic carriers exhibit cognitive dysfunction many decades before the predicted onset of dementia (Geschwind et al, 2001). Understanding the normal function of proteins involved in the etiology of FTD and how they impact not only neurodegeneration but also neural connectivity and function is, therefore, of the utmost importance.…”