Table 3.
Studies reporting neurochemical investigations and neuroanatomy at the cellular level.
| Study | Methods | Sample | Key findings |
|---|---|---|---|
| Akefeldt et al. 1998 [61] | Lumbar puncture: CSF analysed for metabolites of serotonin (5-HIAA), dopamine (HVA) & noradrenaline (HMPG) | 13 participants with PWS (8 males, 0.4–23 y) 5 control groups: 15 typically-developing participants (11 males, 6 aged 3–8 y, 9 aged 18–25 y); 22 typically-developing children (16 males, 3–14 y); 8 children with autism (5 males, 3–13 y); 7 children with mixed neurological diagnoses (6 males, 0.3–15 y); 4 overweight children with ID but not PWS (0 males, 4–15 y) |
Increased levels of 5-HIAA & HVA in PWS compared to all groups, most markedly for serotonin. Significant for 5-HIAA at corrected level compared to all control groups except the overweight and mixed neurological groups at the corrected significance level, but trend found. Significant for HVA at corrected level compared to typically-developing groups and all control participants combined. No association found between increased metabolites in PWS and age, BMI or severity of intellectual disability. |
| Ebert et al. 1997 [62] | Venepuncture: Plasma GABA levels | 14 participants with PWS (6 males, 2–21 y) 9 children with AS (7 males, 2–17 y); 2 control groups: 7 moderately obese participants without ID (5 males, 2–20 y); 5 healthy weight children with ID (4 males, 3–17 y) |
Mean GABA levels in plasmas significantly higher (2-3 times) in both PWS and AS groups than either control group, but no significant difference between PWS and AS groups. |
| Fronczek et al. 2005 [63] | Post-mortem: immunocytochemistry and image analysis system estimation of orexin neuron number in the lateral hypothalamus | 7 hypothalami from individuals with PWS (3 males, 5 adults aged 25–64 y, 2 infants aged 6m & 3 y) 11 control hypothalami, matched for age, sex, post-mortem delay, fixation time and premorbid illness duration. |
No difference in number of orexin neurons in hypothalamus found. |
| Goldstone et al. 2002 [64] | Post-mortem: immunocytochemistry & in situ hybridization to study NPY, AGRP, and NPY mRNA expression in the hypothalamus | 6 obese adults with PWS (2 males, 25–64 y) 4 obese adults without PWS (2 males, 66–76 y) 22 control adults (13 males, 28–90 y) |
Significant decrease of NPY and tendency to decreased NPY mRNA expression in all obese subjects, including PWS, but consistent with literature on inhibition on NPY in obesity. No significant difference in AGRP and NPY staining, or NPY mRNA expression, between PWS and obese adults without PWS. NPY/AGRP neurons show appropriate functioning. |
| Goldstone et al. 2003 [65] | Post-mortem: immunocytochemistry assessment of GHRH neuron number in infundibular nucleus/median eminence complex of the hypothalamus | 6 adults with PWS (2 males, 25–64 y) 2 children with PWS (1 males, 0.5 & 0.75 y) 6 o6 control participants (13 males, 22 adults aged 28–90y, 4 children aged 0.4–0.75 y) |
Higher GHRH neuron number in both control adults and adults with PWS who had prolonged premorbid illness, but no difference between PWS and control or obese adults without PWS. |
| Hayashi et al. 2011 [66] | Post-mortem: immunohistochemical analysis of GABAergic interneurons in superior frontal cortex & OFC, ACh neurons in the nucleus basalis of Meynert & PPN, & orexin-A and vasopressin in the hypothalamus. | 6 month old female with PWS 3 control subjects following fatal pneumonia (2 males, 4 m, 1 y, 6 y) |
GABAergic interneurons in cortex and ACh neurons in nucleus basalis similar in PWS and control samples. No clear abnormalities in orexin and vasopressin neurons in hypothalamus. Marked reduction of ACh neurons in PPN. |
| Lucignani et al. 2004 [67] | Resting state PET: 11C-flumazenil binding to evaluate GABAA receptor functioning. | 6 participants with PWS (2 males, 19.3–29.7 y, mean 24.6 y) 9 typically-developing participants (9 males, mean 25.9 y) |
Significant binding reduction (7%) in cingulate. Reduced binding of ca. 3-6% in PWS in temporal and frontal cortices, and including insula (7%), but not significant when corrected for multiple comparisons. Trend to reduced binding in amygdala, caudate and thalamus (10-14%). Binding potential very similar in hippocampus, putamen and parietal and occipital cortices. |
| Martin et al. 1998 [68] | Lumbar puncture: CSF analysed for levels of oxytocin and vasopressin | 5 participants with PWS (2 males, 16–21 y) 6 typically-developing participants (0 males, 21–28 y) |
Oxytocin levels in CSF significantly higher in PWS, especially in females. Vasopressin levels significant lower in PWS females compared to control females, but not for males or combined sex groups. |
| Pasi et al. 1989 [69] | Post-mortem: immunoradiological assay of beta-endorphin levels in neural tissue | 19 y old female with PWS | No clear beta-endorphin abnormality: rank of levels of beta-endorphin in areas of the brain on which there was prior reference literature (hypothalamus, medulla, periaqueductal grey, pons, & thalamus) was very similar, with the exception of the medulla. |
| Swaab et al. 1995 [70] | Post-mortem: thionine and immunocytochemical staining to assess PVN size and number of oxytocin and vasopressin neurons | 5 adults with PWS (2 males, 22–64 y) 27 control adults (14 males) |
PVN significantly smaller (28%) in PWS, with total cell number reduced by 38%. Oxytocin number significantly decreased in PWS (by 42%) as was volume of PVN containing oxytocin cells (by 54%). No significant difference in number vasopressin neurons between PWS and control samples. |
| Talebizadeh et al. 2005 [71] | Post-mortem: RT-PCR evaluation of gene expression of ghrelin, peptide YY and their receptors in the frontal, temporal, and visual cortices, pons, medulla and hypothalamus | 3 individuals with PWS (0 male, 1 infant aged 1 y, 2 adults aged 32 y) 2 individuals with AS (4y old male, 43y old female) 6 control individuals (3 males, 1–72 y) |
Expression detected in all brain areas in PWS, AS and control samples, with exception of PYY in pons for 1 PWS & 1 control subject. |
ACh: acetycholine; AGRP: agouti-related peptide; AS: Angelman’s syndrome; BMI: body mass index; CSF: cerebrospinal fluid; EMO: early-onset morbid obesity; GABA: gamma-aminobutyric acid; GHRH: growth hormone-releasing hormone; ID: intellectual disability; HMPG: 4-hydroxy-3-methoxyphenyl-ethylene glycol; HVA: homovanillic; m: months; mRNA: messenger ribonucleic acid; NPY: neuropeptid Y; OFC: orbitofrontal cortex; PET: positron emission tomography; PFC: prefrontal cortex; PPN: pedunculopontine nucleus: PVN: paraventricular nucleus; PWS: Prader-Willi syndrome; RT-PCR: reverse transcription polymerase chain reaction; UPD: uniparental disomy; y: years; 5-HIAA: 5-hydroxyindoleacetic acid.