In this small case study we measured several cerebrospinal fluid biomarkers in meningeal tuberculosis. We confirmed the presence of classical TBM CSF findings such as BBB impairment, inflammation and report here, for the first time, very low level of Aβ1–42 [1, 2, 3, 21, 28]. Neuronal damage is a classical feature of TBM due to its devastating inflammation and disruptive process. 14.3.3 positivity was found in 5/13 (38,5%) of TBM; this cellular-cycle protein, previously associated with prionic disease, accumulates in the CSF after neuronal damage especially during bacterial involvement of CNS and it is cleared from the CFS after successful treatment . BBB impairment and IgG synthesis were observed; CSAR and IgG ratios were high in TBM, confirming results in literature where a significant impairment in BBB due to TBM is described [3, 21]. A raised level of neopterin can be found in TBM, denoting intrathecal production by macrophage-derived cells and, as the BBB has a low permeability for peripheral neopterin, it represents a relevant index of local inflammation. [4, 8, 9]
Moreover, we found out that classical markers of TBM disease activity had a good correlation with Aβ1–42: low glucose and higher cells correlates with lower amyloid, BBB damage expressed by CSAR, as well as FTau, resulted higher in lower Aβ1–42 [5, 21]. These findings outline the possibility for amyloid-beta of being a good proxy of precocious disease activity and a potential marker to follow over time. Also, lower Aβ1–42 level was associated with worse outcomes, thus suggesting a possible prognostic of this marker in clinical practice. Additionally, the observation of low levels of Aβ1–42 in patients with TBM is of potential interest and should be interpreted in the context of the recent discovery of a possible antimicrobial role of amyloid-beta [7, 12, 25, 35] and of a hypothetical infectious “trigger” for Alzheimer Disease . Amyloid-beta protein seems to be shed and playing an anti-infective role in response of several infections in a murine model . In vivo low levels of CSF amyloid-beta have been observed in patients with pneumococcal meningitis and other bacterial meningitis [28, 11]
That is critical because observing amyloid metabolic alterations during TBM is perhaps the key passage for understanding amyloid’s antimicrobial role. This may show how amyloid metabolism is potentially altered by several infections, as seen for HSV6 and 7 that have been recently associated with development of AD, probably playing an important role in driving alterations such oxidative damage and progression to accumulation of neurofibrillary tangles.
Several mechanisms regarding the finding of low Aβ1–42, besides amyloid deposition in the brain parenchyma, can be hypothesized. Amyloid-beta levels could be reduced because of the interaction of amyloid-beta fragments with albumin, usually elevated in CSF TBM, thus lowering levels of the free peptide. Additionally, Aβ1–42 can cross the BBB by leaking in CNS and then accumulating (even if it is known that in peripheral tissues Aβ1–40 is prevalent), in the context of increased permeability, thus being lower in the CSF/CNS. Data on the potential measurement of serum amyloid-beta peptides in the setting of Alzheimer’s dementia may confirm this hypothesis [8, 21, 22]. Another mechanism could be an impaired and reduced amyloid-beta clearance from the CNS : the ISF/CSF flow is believed now to be partially convective and through perivascular spaces that can be harmed during tubercular infections of the CNS and systemic inflammation . That could be particularly relevant following the recent discovery of the so called Glymphatic Central Nervous System [19, 23]. TBM it is known to affect the basal anatomic section of the brain with a reduced CSF recirculation, a fibrosant effect and a possible central hypertensive syndrome. In view of these observations it is possible that even the glymphatic recirculation is altered; unfortunately, data are scarce and there are no reliable markers up to date.
To conclude, the analysis regarding the time to normalization for Aβ1–42 in our population deserves an additional remark: relying on our data, only three patients normalized amyloid-beta during follow-up. Patient 4 at day 22, patient 1 at day 190, patient 3 at day 267 (Fig. 3). Acknowledging that data are limited and we were not able to measure these equally for all patients, it is still of great interest that the vast majority of patients did not normalize amyloid-beta while hospitalized nor under treatment; moreover, the time to normalization was not homogenous between patients suggesting a persistent and unpredictable ongoing accumulation and probable undergoing slight but constant and enduring inflammation, which is coherent with TBM physiopathology and such a life-threatening condition. Following a recent article and debate [29, 30], could be tested as a prognostic marker in both pediatric and adult population, backing the routine use of available neuromarkers for both a better tailored approach to patients and in research. An adjunctive information may come from retesting Aβ1–42 levels at the end of therapy (one-year follow-up retesting). To our knowledge, this is the first case showing such low levels of Aβ1–42 in TBM; its accumulation, drove by neuroinflammation related to infections, can be central in understanding neurodegenerative diseases. This study has several limitations: study design lacking an age-matched or Alzheimer’s control group, sample size, impossibility to perform homogenous number of LP at follow-up for all patients and incomplete data on Neurofilaments (NFL). Nevertheless, the finding of low Aβ1–42 concentrations warrant further analysis in controlled settings.