Alzheimer’s Disease: The Great Morbidity of the 21st Century
Neuroangiogenesis (NAG) provides a vascular basis for understanding Alzheimer’s disease, senile dementias and cognitive decline with aging
Cerebral Capillary Density (CCD)
Research on cerebral microvascularity began in the early 1920s with Edward Horne Craigie (1894–1989), a biologist at the University of Toronto, who examined male albino rats from their birth to 13 months of age (day 364). He measured cerebral capillary density in various parts of their brains by counting certain structural features of the capillaries in thinly cut slices (2–6 micrometers thick), where obviously only segments of vessels remain. He used the sum of the lengths of fragments visible in a fixed area of each brain slice over a fixed number of slices, to yield a composite value, Lv in micrometers per cubic micrometer. To exclude arterioles, only vessel fragments with diameters generally smaller than 12 micrometers were included in his measurements. Later investigators employed other indices of capillary morphometry, as outlined in my Journal of Alzheimer’s Disease paper. Below are summarized CCD findings for the four periods outlined previously.
Postnatal period. In young rats Craigie examined the five laminae (Brodmann’s layers) in each of five cortical areas for Lv and found that vascularity in all areas rose rapidly from birth (average of 306) to day 21 (average of 862) but only slowly thereafter.
In the human brain the most rapid growth occurs between ages 3 to 6 years in the frontal lobes and from 6 to 15 years in the temporo-parietal region. Diemer compared the capillary density in the frontal cortex of newborn infants and adults and found the former to be 98.4 capillaries per square millimeter and the latter to be 290 per square millimeter.
Maturity. After the brain’s full development, the functional status of the cerebral microcirculation depends on the maintenance and replacement of capillary endothelial cells. The turnover rates for these cells in animal or human brains have not been reported, but such values for endothelial cells elsewhere in the bodies of various animals are available from studies which employed thymidine labeling of capillary endothelium and autoradiographs of tissue sections. For example, in 1967 Engerman and co-workers found that 0.01 percent of the capillary endothelial cells in the adult mouse retina were labeled after a single injection of tritiated thymidine and interpreted this as a turnover time of three or more years. More recently, based on the “mean of 14 studies” mainly in mice by numerous investigators, Denekamp concluded that the “potential turnover time” of capillaries of “normal tissues” is 60 days. Accepting Denekamp’s mean value of six times per year as a possible turnover number in the human brain and assuming an average life span of 60 years after puberty, I calculate that cells in the cerebral capillary bed undergo replacement 360 times during the average adult’s life. On the other hand, if one adopts Engerman’s three-year estimate of capillary endothelial turnover, then these cerebral capillaries would undergo regeneration 20 times during an average adult lifetime. Whatever the true value, replenishment occurs and is mediated by angiogenic factors in the brain.
Senescence in rats. Craigie found that average value of cerebral capillary density in aged rats rose to a maximum by month 13 in three cortical regions but declined in the two others after month 3 or 5. In regio temporalis CCD rose to 958 micrometers in month 3 but was 880 micrometers by month 13. And in the regio insularis CCD peaked at 856 micrometers during month 5 but fell to 638 micrometers by month 13. Buchweitz-Milton and Weiss recorded values for Lv (sum of capillary lengths in millimeters per cubic millimeter) in the cerebral cortex of “young” rats (8–10 months) as 830 and of senescent rats (28–33 months) as 577. A similar decline in Lv was reported in all other brain areas of the older rats. Klein and Michel measured various neocortical components (neurons, glial cells, vascular tissue) in the frontal and occipital neocortex of young adult rats (6–8 months old) and aged ones (25–27 months old) and found that combined component counts were 448 in the young adult group and 314 for the old rats.
Senescence in people devoid of recognized dementia. Impairment of cerebral capillaries in older persons was observed by Stewart and colleagues. They obtained biopsy specimens from the neocortex and underlying white matter in patients ranging from 20 to 80 years in age who had undergone surgery for glial tumors or corticectomy for intractable epilepsy. As measured by electron microscopy, the wall thickness of capillaries in both gray and white matter was thinner in older subjects than younger ones. The authors interpreted this age-related thinning as due to “a net loss of endothelial cells, with resultant elongation of the remaining cells.”
A deceased cerebral capillary density was reported by William B. Abernethy and colleagues in the paraventricular nuclei of 19 older human subjects, who ranged in age from 30 to 85 years and had no history of psychiatric treatment. Somewhat related is an earlier study by Kuwabara and Cogan, who had noted a decline in the number of endothelial cells “in the capillaries of the peripheral retina in persons past middle life (50 years).”
Senile dementias, mainly Alzheimer’s disease. Bell and Ball measured microvascular densities of capillaries and arterioles in the hippocampus of three groups: normal young persons (mean age of 38 years), normal old (74 years) and Alzheimer’s patients (78 years) and recorded the overall mean values as 129, 108 and 107 millimeters per cubic millimeter, respectively. Fischer et al. examined four areas in normal versus AD brains and found average vascular density indices (rounded off) as follows: basal forebrain, 87 versus 43; hippocampus, 82 versus 50; pre-frontal, 95 versus 75; and motor/sensory, 94 versus 83. And finally, Buée et al. reported the “percentage of the ratio capillary surface area/cortical … field area” for three groups: young controls, 26.32 percent; elderly controls, 18.95 percent; and AD patients, 16.50 percent. This subject has also been extensively reviewed elsewhere.