The patient is a 53-year-old man and a university professor with a bachelor's degree, who visited our cognitive impairment clinic on 23 November 2020, mainly because of "progressive worsening of memory loss for more than 2 years. The patient was found to have reduced responsiveness during communication, was unable to remember things, and repeatedly asked questions about things he was told by his wife 2 years before the consultation. However, his normal work was not affected. One and a half year ago, the patient felt that his memory loss was deteriorating. He often forgot to give lessons to students and needed to record things to help himself remember. His ability to perform daily activities, such as teaching online, sending emails, managing money, and cooking, has declined. He was irritable and had sleep disturbances, which attracted the attention of his family and sent him to the hospital. He had no significant medical history, denying arterial hypertension, diabetes, coronary heart disease (CHD), cerebrovascular disease, and other chronic illnesses. Also, he had no history of infectious diseases such as hepatitis, tuberculosis, and malaria; history of trauma and blood transfusion; and history of food and drug allergy. According to his family, his uncle suffered from memory loss in his 50 s, which gradually progressed to be unable to recognize his family, accompanied by nocturnal sleep disturbances and abnormal behavioral symptoms, but he did not receive formal treatment until his death in his 60 s. The results of physical examination indicated a temperature of 36.5 C, a pulse of 74 times/min, a breathing rate of 19 times/min, blood pressure (BP) of 128/65 mmHg (1 mmHg = 0.133 kPa), no deformity in the thorax, and clear breath sounds in both lungs, with no dry and wet rales. The heart sounds were strong and rhythmic, and no pathological murmur was heard in the auscultation area of each valve. The abdomen was soft, with no pressure pain, and the liver and spleen were not palpable under the ribs. Both lower limbs were not swollen, and there was no deformity of the spinal limbs. Neurological examination showed no abnormalities except for a decrease in time and place orientation, calculation, and recent memory. The frontal lobe release signs of palm-grasping reflex, rooting reflex, and sucking reflex were all negative.
The routine blood, coagulation function, serum immune function, liver and kidney function, lipids, blood glucose, high sensitive C-reactive protein, homocysteine, thyroid function, folic acid, vitamin B12, ferritin, immune panel (hepatitis A, hepatitis B, hepatitis C, syphilis, and HIV), urine routine, and stool routine showed no significant abnormalities. The electrocardiogram showed normal sinus rhythm. The neuropsychological assessment showed a multidomain cognitive decline highlighted by delayed recall deficits, along with emotional irritability and sleep disturbances (Table 1). Brain magnetic resonance imaging (MRI) (November 23, 2020) showed atrophy of the bilateral temporoparietal and posterior cingulate gyrus, and widening of the ventricles, cisterna, brain fissures, and brain sulci (Figure 1). Automated brain tissue segmentation was performed by the Dr. Brain tool to extract multiparameter volumetric measurements from different brain regions (https://cloud.drbrain.net, registration number: 20212210359). The artificial intelligence brain structure imaging analysis showed decreased total white matter volume in the whole brain; decreased volume in the bilateral hippocampus, amygdala, left inferior parietal area, and left temporal pole; and thinning of cortical thickness in the bilateral inferior parietal gyrus, left superior parietal gyrus, left superior limbic gyrus, left precuneus, bilateral middle temporal gyrus, left olfactory area cortex, left posterior cingulate gyrus, and bilateral isthmus (Table 2). Multimodal molecular imaging of 18-fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG PET-CT) results suggested the multiple hypometabolism in the bilateral parietal and combined temporoparietal areas, bilateral temporal lobes, and posterior cingulate gyrus (Figure 2). Cerebrospinal fluid (CSF) Abeta and tau were detected by the enzyme-linked immunosorbent assay (ELISA): beta-amyloid (1-42) (Abeta1 - 42) was 191.15 pg/ml (normal values >651 pg/ml), beta-amyloid (1-40) (Abeta1 - 40) was 7,945.40 pg/ml (normal values >7,000 pg/ml), Abeta1 - 42/Abeta1 - 40 ratio was 0.024 (normal value > 0.05), total tau protein was 635.89 pg/ml (normal value <= 399 pg/ml), and phosphorylated tau181 (p-tau181) protein was 19.8 pg/ml (normal value <= 50 pg/ml). Combined with the medical history, clinical symptoms, and relevant examinations, mild cognitive impairment (MCI) due to AD (multidomain amnesia type) was considered according to the revised consensus for MCI diagnosis from the International Working Group.
Butylphthalide (0.6 g/day) was given orally. At 3 months, the patient's cognitive function and neuropsychiatric symptoms remained stable. At 6 months, immediate memory function began to be impaired and the activity of daily living function has worsened. At 9 months, the patient showed significant personality changes and behavioral abnormalities, manifested by stubbornness, repeated excessive shopping, confabulating, irritability, and disinhibition. At the same time, cognitive function (orientation and calculation) has declined more than before (Table 1). Molecular genetic screening was performed by whole-genome sequencing and repeat primer PCR: the patient carried a TBK1 c.704 A>T (p.Tyr235Phe) heterozygous mutation (Figure 3) with an APOE genotype of epsilon2/epsilon4. Further validation of the locus by Sanger sequencing was performed in the proband's family, and both his mother and daughter were wild type. Accordingly, the medication was adjusted to memantine and donepezil.