Cereb Cortex︱Li Qiang/Mingdong's research group jointly revealed the key white matter structural lesions in patients with mild cognitive impairment

Author ︱ Zhou Yu, edited by Si Xiaopeng ︱ Wang Sizhen Mild cognitive impairment (MCI) is the preclinical stage of Alzheimer's disease (AD)[1, 2]
.

The annual AD conversion rate of MCI can reach 10%-15%, which is much higher than the conversion rate of healthy elderly (1-2%) [3]
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AD progression is irreversible, and screening for MCI is helpful for early intervention and delaying AD progression [4, 5]
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Therefore, early diagnosis of MCI is of great value in screening for high-risk AD
.

 β-Amyloid (Aβ) and Tau protein deposition appeared the earliest as biomarkers in the development of AD [6], which can be used for early screening of MCI
.

However, based on radioisotope tracing and the extraction of cerebrospinal fluid to collect molecular markers such as Aβ and Tau protein, it is difficult to widely implement early MCI screening [7]
.

Therefore, exploring new non-invasive biomarkers is helpful for large-scale MCI screening
.

During the development of AD, demyelination of cerebral white matter fibers occurs earlier [10, 11] than the structural atrophy of gray matter and abnormal brain functional networks [8, 9]
.

The diffusion magnetic resonance imaging (dfMRI) method can detect the subtle structural changes of white matter fibers, which is helpful for non-invasive large-scale screening of MCI patients [12]
.

However, it is not fully understood which white matter tracts are abnormal in the brains of MCI patients
.

 Compared with the global degeneration of white matter fibers in AD patients, the white matter fibers in MCI patients are characterized by selective degeneration in the limbic system [13, 14], among which the fornix [15] and the posterior cingulate gyrus [16] connected to the hippocampus are in MCI patients.
The earliest injury occurred
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In addition, the study of white matter structural network in MCI patients showed that the pathological changes from MCI to AD target key nodes such as the hippocampus and medial temporal lobe [17], and spread to the whole brain through the limbic system white matter fiber pathway [18-20]
.

Among them, the hippocampus, as an important part of the limbic system, is responsible for cognitive functions such as memory [21]
.

The main clinical manifestation of MCI patients is memory impairment [22], and the study of white matter fibrous lesions connected to the hippocampus can help to detect MCI in time
.

The current study focuses on the degeneration of white matter in the limbic system in MCI patients, and there is insufficient evidence for the degeneration of white matter fibers connected to the hippocampus in addition to the limbic system in MCI patients
.

 In addition to memory deficits, MCI patients also have executive dysfunctions such as attention and information processing speed [23]
.

The thalamus acts as a relay station between lower neurons and the cerebral cortex, and there are extensive white matter fiber connections with the subcortical nuclei and the cerebral cortex [24, 25]
.

In addition to forming a Papez circuit with subcutaneous nuclei in the limbic system such as the hippocampus, the thalamus is responsible for memory processing [26]; the thalamus is also connected to the frontal and parietal cortex through projection nerve tracts [27], and is mainly responsible for emotional and cognitive regulation.
[28]
.

Although studies have found that the white matter fibers connecting the thalamus and the subcutaneous nucleus hippocampus are degenerated in MCI [29], it is still unknown whether the white matter connection between the thalamus and higher cortex such as frontal and parietal cortex is degenerated in MCI
.

 In addition, there are studies showing that
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Some patients in the MCI stage will be accompanied by depression [30-32], and depression is an important factor aggravating the transformation of MCI to AD [33-35]
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A study of the white matter of the brain of patients with depression found that the damage of the projection fiber white matter pathway between the thalamus and the medial frontal lobe leads to the interruption of information transmission between the cortex and the subcortical structure, which changes the emotional response to external stimuli and increases the possibility of depression [ 36, 37]
.

Whether there is depression-related white matter fiber degeneration in degenerated-impaired white matter fibers during the MCI stage also needs to be further clarified
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 On December 4, 2021, Tianjin University's School of Microelectronics and the Ministry of Medicine jointly published an article entitled "Hippocampus- and thalamus- related fiber-specific white matter reductions in mild cognitive impairment" on Cerebral Cortex, an important international journal of brain science.

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Tianjin University is the first author of the paper
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Doctoral student Zhou Yu and Associate Professor Si Xiaopeng from the Medical Department are the co-first authors of the paper, and Professor Li Qiang from the School of Microelectronics, Associate Professor Si Xiaopeng and Professor Ming Dong from the Medical Department are the co-corresponding authors of the paper
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For the first time, the study found white matter degeneration in specific nerve tracts such as the hippocampus-temporal lobe and the thalamus in patients with mild cognitive impairment
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The mean diffusivity of hippocampal-temporal and thalamic-related tracts was significantly higher in MCI and could be used to effectively classify the two groups; degenerate tracts detected by DTI indicators, especially hippocampal-temporal tracts, compared with normal tracts Lobar tracts were significantly more correlated with cognitive scores; thalamic-related tracts were significantly more correlated with depression scores within MCI than hippocampal-temporal tracts
.

This study provides new biomarkers for early imaging diagnosis of AD
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In order to find out the most important white matter pathways in the MCI stage, the researchers recruited patients with early mild cognitive impairment (MCI group) and healthy controls (NC group) to define functional networks using functional connectivity with the hippocampus as a seed point.
, based on diffusion tensor imaging (DTI) to track fibers, combined with structural connectivity for fiber tracking, to construct a probability map of fiber bundles related to the hippocampus of the brain by means of cohort analysis
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Based on this probability map, the diffusion index on each subject's nerve bundle was extracted from the map of the DTI diffusion imaging index
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Then, differences between groups were used to analyze all nerve tracts, to compare the correlation of cognitive scores, and to evaluate the classification accuracy of machine learning, so as to find out the abnormal white matter fiber tracts in MCI population and the brain network composed of these white matter pathways
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Table 1 Demographic and neuropsychological information of the subjects (source: yu zhou et al.
, Cereb Cortex, 2021) The information in Table 1 is the test scales currently used by doctors
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Mainly include Mini-mental State Examination (MMSE), Cognitive Abilities Screening Instrument (CASI), Geriatric Depression Scale (GDS), and Clinical Dementia Rating Scale (Clinical Dementia Rating, CDR)
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Figure 1 shows the tracking of white matter nerve tracts at the MCI and NC group levels and the extraction steps of DTI parameters for each nerve tract at the individual level
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Figure 1.
Flow chart of group white matter tract pathway and individual tract DTI parameter extraction (Source: yu zhou et al.
, Cereb Cortex, 2021) First, the authors analyzed the inter-group differences of the same tract DTI parameters between MCI and NC difference
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The results showed that the MD values ​​of the tracked 28 nerve bundles were all greater than those of NC; and the MD of 14 nerve bundles was significantly higher in the MCI group than in the NC group (Figure 2)
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These results suggest that MD parameters of nerve bundles may serve as effective biomarkers for MCI
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Figure 2 Statistical difference analysis of MD parameters of all white matter nerve bundle pathways between MCI and NC (Image source: yu zhou et al.
, Cereb Cortex, 2021) Next, the authors analyzed the differences of all nerve bundles at the overall level
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Figure 3A is a transparent cerebral hemisphere model in the MNI152 space with abnormal white matter tracts, showing the damaged tracts of a patient with MCI
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Figure 2B shows the network node diagram based on the ROIs connected by the hippocampus, thalamus and nerve bundles, showing that the hippocampus and the thalamus are important nodes in the MCI white matter damage network
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Figure 3C is a quantitative analysis of the differences between groups in the hippocampus-temporal lobe, thalamus-related and normal nerve bundles, indicating that the hippocampus-temporal lobe and thalamus-related nerve bundles were significantly degenerated
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Figure 3 D and E are the quantitative analysis of the difference between the left and right brain of the hippocampus-temporal lobe and thalamus-related nerve bundles, respectively, showing that the MCI hippocampus-temporal lobe nerve bundles were bilaterally damaged in white matter, and the thalamic-related nerve bundles showed left-brain lateralization
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Overall, these results suggest that MCI patients have bilateral hippocampal-temporal nerve tracts and left thalamus-related white matter damage (Fig.
3)
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Figure 3 Spatial distribution and statistical comparison of white matter fiber tract damage in MCI
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(Source: yu zhou et al.
, Cereb Cortex, 2021) The author further obtains the feature set required for classification by exploring the classification performance of a single nerve bundle DTI parameter for MCI and NC in machine learning, and assigns each The MD of all voxels in the same nerve tract is tested for dimensionality reduction, and appropriate parameters are selected to obtain better classification results, and the performance of different nerve tracts for MCI classification is evaluated
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The results showed that the classifier characterized by all voxel MD values ​​in the hippocampus-temporal lobe and thalamus-related tracts had high separability (Fig.
4)
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Figure 4 Quantitative analysis of the classification performance of hippocampal-temporal lobe nerve bundles and thalamus-related nerve bundles (Source: yu zhou et al.
, Cereb Cortex, 2021) Based on the aforementioned results (Figure 2-4), the author also analyzed the MCI and NC The relationship of differential neural tracts to cognitive behavior
.

It was found that between the quantitative analysis of the three groups of nerve tracts, the hippocampus-temporal tracts (HIP-Temporal tracts) and the thalamus related tracts (Thalamus related tracts) MD parameters were correlated with MMSE scores.
There were significant differences with normal nerve bundles (Fig.
5A)
.

The thalamus-related tracts were significantly different from normal tracts when the broader CASI scale was used (Fig.
5B)
.

These results (Fig.
5) suggest that damage to the hippocampal-temporal lobe and thalamus-related fascicles is associated with cognitive decline in MCI, and the hippocampal-temporal lobe is more effective in reflecting cognitive decline in MCI
.

Figure 5 Statistical analysis of the correlation coefficient between MD parameters and cognitive scores between different nerve bundle groups (Source: yu zhou et al.
, CerebCortex, 2021) At the end of the article, the author explored the relationship between the MD parameters of a single nerve bundle and the depression scale.
correlation
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The results confirmed that white matter damage in Thalamus related tracts was significantly associated with depression compared with HIP-Temporal tracts in MCI patients (Fig.
6)
.

Figure 6 Statistical analysis of correlation coefficients between MD parameters and depression scores between thalamus correlation and hippocampal-temporal lobe tracts (Source: yu zhou et al.
, Cereb Cortex, 2021) Conclusion and discussion of the article, inspiration and prospect of this research finding , for MCI stage subjects, the mean diffusivity (MD) is more sensitive than the fractional anisotropy (FA) to reflect the damage to the white matter of the fiber bundles
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Therefore, compared to FA parameters of nerve bundles, MD parameters may serve as effective biomarkers for MCI
.

Bilateral hippocampal-temporal nerve bundle injury is an important biomarker of MCI
.

Therefore, the differences in MD parameters between the MCI and NC groups, the classification results of single nerve tracts, and the correlation between MD parameters and cognitive behavior all indicate that the damage of the bilateral hippocampal-temporal lobe tracts of white matter is an important biomarker for MCI.

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Hippocampal-temporal lobe nerve bundle damage can reflect the early structural lesions of MCI
.

The researchers found for the first time the damage of the hippocampal-temporal lobe nerve bundle in MCI.
Combined with previous studies [38-40], the researchers speculated that HIP is the early pathway of the white matter network in MCI lesions
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Therefore, it provides a new biomarker for the subsequent diagnosis of MCI
.

Thalamus-related nerve bundle damage is an important biomarker of MCI
.

The researchers demonstrated that the damage of left thalamus-related nerve bundles and white matter is an important biomarker of MCI from three aspects: differences between groups, classification results, and cognitive-behavioral correlation
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The thalamus-associated nerve tract is a key pathway of white matter damage between the subcortical nuclei and the cortex during the MCI stage
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The thalamus is the relay station between the subcortical nuclei and the cerebral cortex.
The researchers speculated that the white matter damage of the thalamus-related nerve bundles in the MCI stage may lead to the interruption of information between the subcortical nuclei and the cerebral cortex
.

Hippocampal-temporal lobe nerve bundle white matter damage can significantly reflect the cognitive decline of MCI patients
.

In the future diagnosis of MCI, the use of hippocampal-temporal lobe white matter damage as a biomarker can objectively reflect the decline of patients' cognitive ability
.

In addition, the researchers also found that the thalamus-related tracts of MCI white matter injury tracts were associated with depressive behavioral performance
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Their study confirmed that damage to the white matter of the thalamus-related tracts is associated with both MCI and depression
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 An open question in MCI is characterizing the underlying pathological lesions of the disease
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While the current work focuses on differences in certain white matter pathways in MCI, further understanding of the correlation between white matter degeneration and other disease markers is also warranted
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In the future, the authors plan to employ a multimodal approach to confirm different MCI biomarkers
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Collectively, this study refines the theory that AD abnormal white matter networks propagate along specific white matter pathways that could provide targeted interventions on the hippocampal-temporal tracts as well as thalamic-related tracts
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Link to the original text: https://doi.
org/10.
1093/cercor/bhab407 Zhou Yu (first from left) first author; Si Xiaopeng (second from left) first author and corresponding author; Ming Dong (second from right) corresponding author; Li Qiang (first from right) corresponding author (photo courtesy of: Li Qiang's Laboratory, School of Microelectronics, Tianjin University and Mingdong Laboratory, Tianjin University School of Medicine and Engineering) Selected previous articles [1] Alzheimers Dement, Yao Jinjing et al.
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Plate making︱Wang Sizhen End of this article