As expected, a significant negative relationship between ventricular volume and CSF Aβ levels existed for the ADNI cohort as a whole. AD patients exhibited greatest ventricular volumes and lowest CSF Aβ levels, healthy controls had the smallest ventricles and highest CSF Aβ levels, whereas MCI patients fell in between on both of these measures. This finding is consistent with widely accepted thinking regarding the relationship between CSF Aβ levels and neuropathological findings in AD.[22
We also expected that this relationship would be strongest for patients with AD, but surprisingly found the opposite relationship when only the AD group was considered. This distinction between the relationships observed when the entire cohort is analyzed versus when AD patients alone were considered is somewhat paradoxical, but may point to important issues regarding the relationships between biomarkers and AD pathogenesis. Specifically, the neuropathology occurring at different stages of AD may produce a different relationship between CSF Aβ and ventricular volume when only people with preclinical or well-established AD are considered.
Overall these results suggest the possibility that Aβ sequestration in brain occurs very early in the prodromal stage of AD, and that by the time people reach the stages of MCI and AD, CSF Aβ dynamics are less operative, and tau sequestration is more active. Another possible explanation is that dementia patients most likely to have a significant association between Aβ and ventricular volume, those with symptoms and radiological signs of NPH, were excluded from the ADNI cohort.
As predicted, CSF tau concentration was more significantly related to whole brain volume than ventricular volume in MCI subjects; however, we were surprised not to see a similar relationship in AD subjects. We suspect that a ceiling effect for this relationship is reached in pathologically well-established AD. To illustrate this point, among APOE ε4 positive subjects, CSF tau increased by 48% between normal and MCI groups, but only by 2% between MCI and AD groups, while VBR increased 25% between normal and MCI groups, and by 13% between MCI and AD groups.
Our findings partially replicate another recent study showing a relationship between elevated levels of CSF tau and ptau181
and whole brain volume in a mixed group of 21 subjects with very mild (CDR 0.5) AD and 8 subjects with mild (CDR 1.0) AD. Among 69 cognitively normal subjects CSF Aβ-42 was positively correlated with whole brain volume. Ventricle volume and VBR were not examined, however, limiting comparison with the present study.[32
The most interesting finding in our study was the negative relationship between Aβ levels and ventricular volume in normals who were positive for the APOE ε4 allele. No significant relationship was found for APOE ε4 positive MCI subjects, suggesting that there is a transition state, when subjects at genetic risk for AD may be sequestering Aβ in the brain mainly during the prodromal stage of the disease. Along similar lines, amyloid deposition in brain has been shown by PiB amyloid PET imaging studies to occur frequently in cognitively normal elders, however, the causes and prognostic significance of such cases of early amyloid deposition are unknown.[33
We propose that altered CSF-blood-brain barrier functions may account for these complex relationships. There is increasing evidence of blood-brain barrier compromise[34
] as well as microvascular damage occurring early in AD.[22
] Apolipoprotein E is essential for both blood-brain barrier integrity and for deposition of fibrillar Aβ. Both APOE and Aβ are ligands for low-density lipoprotein receptor-related protein 1 (LRP-1), a major transporter of Aβ out of brain, and all three proteins are located in plaques. Most plaques are in close proximity to the cerebral microvessels, leading to potentially complex interactions affecting clearance of Aβ. In AD, LRP-1 is downregulated at the blood-brain barrier, which is likely one of the mechanisms of reduced Aβ clearance from the brain.[37
] There is evidence to suggest that APOE ε4 enhances vascular and parenchymal deposition of Aβ in the brain[38
] and may influence both transport and permeability of the blood-brain barrier.[34
CSF protein concentration was consistently higher in AD compared to MCI and controls. This likely reflects enhanced blood-brain barrier permeability to albumin, but there was no correlation between blood-brain barrier function, measured as the CSF total protein level, and any brain or ventricular volume. This finding suggests that blood-brain barrier dysfunction is not directly related to brain atrophy. Aβ-induced disruptions of blood-brain barrier and choroid plexus permeability and transport would be expected to destabilize interstitial and CSF dynamics (and ventricle size) thereby impairing brain metabolism and blood flow.[40
Enhancement of vascular amyloid deposition by APOE ε4 in arachnoid granulations may have a role in reducing Aβ clearance from brain via CSF circulation. This may account for the observation of increased APOE ε4 allele frequency in NPH patients with dementia [42
] and a role for hydrocephalus in the pathogenesis of AD in some patients. Alternatively APOE ε4 may serve as just a marker of earlier onset and more severe AD pathology and not be directly involved in the mechanisms of Aβ clearance via CSF. In further support of a hydrocephalic mechanism for AD is a recent report of Aβ42
and hyperphosphorylated tau pathology occurrence in a kaolin-induced hydrocephalus model of the aged rat.[43
Little is known about compartmentalization of tau in the course of AD, but this data suggests that as neurodegeneration becomes established by cascading pathogenic events, tau becomes sequestered at a later time in those with well-established disease. Tau sequestration in AD may be related to similar mechanisms described previously for Aβ, which occur much earlier than tau in the pathogenic cascade.
Finally, among APOE ε4 negative controls we found a negative relationship between CSF tau and ventricular volume. In this group, age and hippocampal volume were also associated with tau levels, suggesting that age–related atrophy rather than APOE genetic mechanisms may be driving this relationship. Since this group of subjects likely includes many who would never go on to develop AD, the relevance of this relationship to our understanding of biomarkers for AD is limited.
The results of this study should be interpreted with great caution for a number of reasons. The measure of ventricular volume is a global measure of the entire ventricular system. We cannot exclude the possibility that the ventricle volume is merely a proxy for brain atrophy in specific adjacent brain regions such as the medial temporal lobe, which could affect mainly the temporal horn. While the lack of relationship to brain volume in this area in our APOE ε4 positive subjects argues against this possibility, further analyses using segmented ventricle volumes [45
] and ventricular shape data [46
] could provide more definitive evidence for a primary role of ventricular pathology leading to Aβ deposition.
The analyses here were only cross-sectional, due to the limited availability of longitudinal CSF biomarker data in ADNI. Future studies examining sequential changes in biomarkers compared to brain and ventricular volumes in prodromal AD may shed more light on the mechanisms we propose based on baseline data.
Also to be noted, the sample size of 21 in the APOE ε4 positive control group is particularly small. While the relationship between ventricle/brain ratio and CSF Aβ is one of the most interesting observations, these results need verification from studies involving larger samples of older cognitively normal subjects.
Experimental evidence using animal models of hydrocephalus and APOE may shed light on the exact nature of these relationships. If indeed altered CSF clearance mechanisms in the prodromal stage of AD caused by interaction of APOE ε4 and epithelial/vascular function in the choroid plexus and/or arachnoid villi leads to sequestration of Aβ in the brain, setting off a cascade of pathologic events, then efforts to interrupt these mechanisms may prove fruitful in disease prevention.
While this exploration of the ADNI data provides evidence of a potential hydrocephalic mechanism early in AD for some patients as well as a potential explanation of amyloid deposition in NPH, we were unable to examine actual CSF production, which is reduced in aging and AD,[13
]and how this too may affect Aβ, tau, or other brain-derived proteins. These are rich areas of potential future research.
An alternative explanation to the proposed obstructive hydrocephalic mechanism is that enlarged ventricles relative to the rest of brain tissue reflect central atrophy involving white matter volume changes which are more dramatic in APOE ε4 carriers. This could be explored further by examining volumetric measurements of white matter on MRI in comparison to CSF biomarkers.
Ventricular volume [45
] and VBR change [49
] in aging, MCI, and AD is emerging as an important biological indicator of disease progression. As previously mentioned, VBR has been shown to be a more robust correlate of cognitive function in AD and MCI than other whole brain measures. The reason for this significant relationship is not well understood but deserves further investigation, as VBR may be a useful biomarker outcome for early disease intervention and prevention trials, particularly for those at genetic risk due to APOE ε4 genotype.