Synapse loss in frontal cortex biopsies in Alzheimer's disease: Correlation with cognitive severity

Abstract

Ultrastructural studies of biopsied cortical tissue from the right frontal lobe of 8 patients with mild to moderate Alzheimer's disease (AD) revealed that the number of synapses in lamina III of Brodmann's area 9 was significantly decreased when compared with the number in age-matched control brains (n = 9; postmortem time, less than 13 hours). Further decline in synaptic number was seen in age-matched autopsied AD specimens. In the AD brains there was significant enlargement of the mean apposition length, which correlated with degree of synapse loss; as synapse density declined, synapse size increased. The enlargement of synapses, coupled with the decrease in synaptic number, allowed the total synaptic contact area per unit volume to remain stable in the patients who underwent biopsy. In autopsied subjects who had AD, there was no further enlargement of mean synaptic contact area. There was a significant correlation between synapse counts and scores on the Mini-Mental State examination in the patients who underwent biopsy. Lower mental status scores were associated with greater loss of synapses. Choline acetyltransferase activity was significantly decreased in the biopsied group and declined further in the autopsied specimens of AD. There was no relationship between choline acetyltransferase activity and scores on the Mini-Mental State examination or synapse number. There is evidence of neural plasticity in the AD neuropil; synaptic contact size increased in patients who had biopsy and possibly compensated for the numerical loss of synapses. But by end stage of the disease, the ability of the cortex to compensate was exceeded and both synapse number and synaptic contact area declined.(ABSTRACT TRUNCATED AT 250 WORDS)

Motion‐related artifacts in structural brain images revealed with independent estimates of in‐scanner head motion

“…Of note, T1w scans flagged by a combination of $\overline{\mathit{F}\mathit{D}}$ and QC ratings: (1) increased with increasing age, and (2) exhibited considerably reduced global and regional estimates of gray matter volume and thickness. Reductions in gray matter volume and thickness are well documented as a hallmark of healthy aging and cognitive decline [DeKosky and Scheff, 1990; Dickerson et al, 2008, 2012; Sowell et al, 2003]. We suggest that these effects may in some cases be overestimated, particularly in certain brain locations, by the inclusion of biased estimates from T1w structural scans with motion artifacts.…”

Reversing Synapse Loss in Alzheimer's Disease: Rho-Guanosine Triphosphatases and Insights from Other Brain Disorders

“…Mounting evidence suggests that these are due to prominent synapse loss, particularly in the hippocampus and throughout the cortex [16][17][18][19][20], the principal areas affected in AD, and not to the loss of whole neurons. In fact, dendrite and synapse loss show a much stronger correlation with the associated cognitive decline than do neurofibrillary tangles or frank neuronal degeneration [17].…”

“…Mounting evidence suggests that these are due to prominent synapse loss, particularly in the hippocampus and throughout the cortex [16][17][18][19][20], the principal areas affected in AD, and not to the loss of whole neurons. In fact, dendrite and synapse loss show a much stronger correlation with the associated cognitive decline than do neurofibrillary tangles or frank neuronal degeneration [17]. Additionally, the loss of synapses is often significantly more pronounced than would otherwise be predicted from simple neuronal loss, firmly placing synaptic dysfunction as a driver of AD-related cognitive decline rather than a byproduct [16][17][18].…”

“…In fact, dendrite and synapse loss show a much stronger correlation with the associated cognitive decline than do neurofibrillary tangles or frank neuronal degeneration [17]. Additionally, the loss of synapses is often significantly more pronounced than would otherwise be predicted from simple neuronal loss, firmly placing synaptic dysfunction as a driver of AD-related cognitive decline rather than a byproduct [16][17][18]. At its core, AD is a disease of synapses.…”

CSF neurogranin or tau distinguish typical and atypical Alzheimer disease

“…Their plasticity underlies learning and memory, through mechanisms including long‐term potentiation (LTP) and depression (LTD). There is substantial evidence that synapse loss is an early event in Alzheimer's disease (AD), preceding neuronal cell death and cognitive decline and is found throughout the neuropil without any clear relation to amyloid plaques 1, 2, 3. Biomarkers of synapse dysfunction or loss could potentially be useful in identifying Alzheimer's disease patients in the predementia stage as well providing information about disease pathophysiology that could have utility in clinical drug trials.…”