Alzheimer's & Dementia: Temporal dynamics predict symptom onset and cognitive decline in familial frontotemporal dementia

Before the onset of symptoms of neurodegenerative diseases, neuropathological and structural changes accumulate over many years
.
Understanding the timing and consequences of these changes in clinical syndromes is key
to explaining the heterogeneity of progression and risk stratification for asymptomatic individuals in preventive clinical trials.
Functional network integrity has been found to be important in maintaining cognitive performance in individuals at risk of dementia, and the inference is that loss of network integrity may indicate the onset of symptoms and predict cognitive decline
.
Hereditary frontotemporal dementia (FTD) provides an opportunity to characterize functional networks
throughout the disease course.

About one-third of FTD patients have an autosomal dominant family history and mutations in three genes are the main cause of these cases: chromosome 9 open reading frame 72 (C9orf72), granulin (GRN).
and microtubule-associated protein tau (MAPT).

The resulting phenotype is heterogeneous, with behavioral variability FTD (bvFTD) being the most common clinical manifestation
.

David J.
Whiteside et al.
tested whether changes in the functional network predicted cognitive decline in familial frontotemporal dementia (FTD) and the transition
from symptomatic prodromal to symptomatic disease.

The research team recruited 36 participants in behavioral variability FTD (bvFTD) and 34 controls
.
To test the hypothesis, 198 carriers of symptomatic FTD mutations, 341 carriers of presymptomatic mutations, and 329 family members
without mutations were studied.
The functional network dynamics, clinical severity and longitudinal clinical progress
between groups were compared.

The study found a characteristic pattern
of changes in the dynamic network of FTD associated with neuropsychological disorders.

Figure 1.
Network dynamics
of hereditary frontotemporal dementia.
(A) Average activation plot
of the six states.
(B) The occupancy rate of each state is different, with the occupancy rate of states 2 and 4 increasing and the occupancy rate of states 3 and 5 decreasing.

(C) Transition and persistent probability change in frontotemporal dementia (FTD
).
The blue line indicates a significant decrease in conversions in FTDs, and the red line indicates a significant increase
in conversions.
These figures show the absolute percentage
increase or decrease in the FTD.

Figure 2.
Network dynamics that occur in the late presymptomatic period
.
(A) Component load
of principal component analysis (PCA) for state occupancy.
(B) During longitudinal follow-up, the component scores of converts (scanned before the latest symptoms) were significantly increased
compared to those who did not transition to the symptomatic period.
(C) Partial occupancy by status, with an increase
in converters showing state 2 (significant) occupancy.
(D) Status 2 occupancy of
all converters.
(E) State 2 occupancy rates in presymptomatic mutation carriers (PSCs) are nonlinear with
age compared to non-carriers (NCs).

In presymptomatic mutation carriers, this network dynamic pattern is found to a greater
extent in patients who subsequently transition to the symptomatic phase.

Figure 3.
Cognitive decline
in symptomatic participants.
(A) The baseline component score predicted subsequent cognitive decline in participants with symptoms on the Mini-Mental State Test (MMSE), associated with
Digit Span and Trail Making Test B (TMTB).
(B) In a series of clinical and neuropsychological tests, baseline state 2 occupancy predicts subsequent cognitive decline
in symptomatic patients.

 Baseline network dynamics predicted future cognitive decline
in symptomatic participants and older presymptomatic participants.

 The study shows that sporadic and familial FTDs disrupt the temporal dynamics of large-scale brain networks, with characteristic changes during both the symptomatic period and the late presymptomatic period of the disease.

Increased significance and default network occupancy, and decreased proportion of time spent in the primary cortex and subcortical regions: this change correlates with clinical and neuropsychological markers of disease severity.

Changes in temporal dynamics occur close to the onset of disease and predict the onset and worsening of clinical syndromes, such as :(1) increased component scores in those patients who subsequently transition to symptomatic periods during follow-up, and (2) increased rates of cognitive and clinical decline in symptomatic and older presymptomatic participants with symptomatic and higher component
scores.

Original source

Temporal dynamics predict symptom onset and cognitive decline in familial frontotemporal dementia.
https://doi.
org/10.
1002/alz.
12824