Hydrocephalus, Normal Pressure

Self-report variables relating to social factors that could be considered as deficits were identified separately in the CSHA and the NPHS (Table 1). Deficit selection was guided by two imperatives. First, we aimed to include a broad representation of factors that influence and describe an individual's social circumstance. These factors were based on previous studies which have suggested that they are relevant (e.g. social support, social engagement, sense of mastery/control over one's life circumstances).[1] (link)–[4] (link), [8] (link), [21] As part of a holistic description of social vulnerability, socioeconomic status (e.g. income adequacy, home ownership – addressing both wealth and housing security – and educational attainment) was also included,[22] (link), [23] (link) as these factors also influence vulnerability to insults with the potential to impact their health status. The two instrumental activities of daily living items included (ability to use the telephone and to get to places outside of walking distance) explicitly relate to an individual's ability to maintain social ties and participate in their community, and were therefore included in the social index. Second, working within the constraints of secondary data analysis, we aimed to make the measure of social vulnerability as sensible and as broadly applicable and comparable between datasets as possible.
Each respondent was assigned a score of 0 if a binary social deficit was absent and 1 if it was present; intermediate values were applied in cases of ordered response categories. For example, an individual scored 1 on the “lives alone” deficit if he/she reported living alone, and 0 if he/she did not. On the “do you ever feel you need more help” deficit, which had three response categories, possible scores were 0 if the answer was “never”, 0.5 for “sometimes” and 1 for “often”. As such, vulnerability on each deficit was mapped to the 0–1 interval. For each individual, a social vulnerability index was constructed using the sum of the deficit scores, yielding a theoretical range of 0–40 in the CSHA and 0–23 in the NPHS. To allow better comparison between the datasets, each with a different number of social deficits, the social vulnerability index was also calculated as a proportion of the total number of deficit items by dividing the sum of deficit scores by the number of deficits considered (40 in the CSHA and 23 in the NPHS), yielding an index with a theoretical range of 0–1.

Frailty was operationalized analogously to the social vulnerability index, in both the CSHA and NPHS, as described elsewhere.[17] (link), [24] (link) In brief, deficits representing self-reported symptoms, health attitudes, illnesses, and impaired functions (Table S1) were identified and given scores mapping to the 0–1 interval as described above, with a greater score corresponding to worse health status. The social vulnerability and frailty indices were mutually exclusive; no deficits overlapped.

Individuals who were diagnosed as SCD were eligible for the study. Subjects who visited the hospital due to persistent cognitive worsening and were diagnosed with SCD after dementia work-ups are consecutively recruited. The dementia work up included detailed neuropsychological test battery, MRI, and routine blood sampling for syphilis, thyroid function, vitamin B deficiencies, and apolipoprotein epsilon genotyping. The inclusion criteria were as follows (Table 2): Age ≥ 60 years of age; Existence of persistent self-reported cognitive complaints; Normal performance (above −1.0 standard deviation [SD] of norms) on all subtests of neuropsychological test battery named Seoul Neuropsychological Screening Battery (SNSB);^{[4 ]} Clinical dementia rating (CDR) score of 0;^{[5 ]} Agreement to participate in the study and could visit the hospital for annual evaluations. The exclusion criteria were the following: Mild cognitive impairment (MCI) or dementia; Brain lesions known to cause cognitive impairment (tumor, stroke, or subdural hematoma); Any neurological disorders such as Parkinson’s disease, Huntington’s disease, epilepsy, or normal pressure hydrocephalus; Major psychiatric disorders such as uncontrolled depression, schizophrenia, alcoholism, or drug dependency; Abnormal blood laboratory findings such as abnormal thyroid function, low vitamin B12 or low folate, or positive syphilis serology, and; Hearing loss that is impossible to perform phone-based cognitive tests.

Mice were purchased from the Jackson Laboratory (GSK-3βFL, Stock No 029592; NPHS-Cre, Stock No 008205), and the podocyte-specific GSK-3β-KO mice were generated as described previously [35 (link)]. The grouping and treatment protocols used in the aforementioned lncRNA Dlx6-os1 overexpression study with the db/m mice were adapted for this experiment.