Understanding factors associated with the trajectory of subjective cognitive complaints in groups with similar objective cognitive trajectories.

BACKGROUND: Cognitive complaints are often regarded as an early sign of Alzheimer's disease (AD) but may also occur in several other conditions and contexts. This study examines the correlates of cognitive complaint trajectories over a 5-year period in individuals who shared similar objective cognitive trajectories. METHODS: We analyzed a subsample (n = 1748) of the MEMENTO cohort, consisting of individuals with subjective cognitive decline or mild cognitive impairment at baseline. Participants were stratified based on their latent MMSE trajectory over a 5-year period: "high and increasing," "subtle decline," and "steep decline." Within each of the three strata, we used a latent-class longitudinal approach to identify distinct trajectories of cognitive complaints. We then used multiple logistic regressions to examine the association between these complaint trajectories and several factors, including AD biomarkers (blood pTau/Aß42 ratio, cortical thickness, APOE genotype), anxiety, depression, social relationships, a comorbidity-polypharmacy score, and demographic characteristics. RESULTS: Among participants with high and increasing MMSE scores, greater baseline comorbidity-polypharmacy scores (odds ratio (OR) = 1.30, adjusted p = 0.03) were associated with higher odds of moderate and increasing cognitive complaints (as opposed to mild and decreasing complaints). Baseline depression and social relationships also showed significant associations with the complaint pattern but did not survive correction for multiple comparisons. Among participants with subtle decline in MMSE scores, greater baseline depression (OR = 1.76, adjusted p = 0.02) was associated with higher odds of moderate and increasing cognitive complaints (versus mild and decreasing). Similarly, baseline comorbidity-polypharmacy scores and pTau/Aß42 ratio exhibited significant associations, but they did not survive correction. Among participants with a steep decline in MMSE scores, greater baseline comorbidity-polypharmacy scores increased the odds of moderate complaints (versus mild, OR = 1.38, unadjusted p = 0.03, adjusted p = 0.32), but this effect did not survive correction for multiple comparisons. CONCLUSIONS: Despite similar objective cognitive trajectory, there is heterogeneity in the subjective perception of these cognitive changes. This perception was explained by both AD-related and, more robustly, non-AD-related factors. These findings deepen our understanding of the multifaceted nature of subjective cognitive complaints in individuals at risk for dementia and underscore the importance of considering a range of factors when interpreting cognitive complaints.

Pilot Study Assessing the Impact of Intrathecal Administration of Variants AAV-PHP.B and AAV-PHP.eB on Brain Transduction in Adult Rhesus Macaques.

Adeno-associated virus (AAV) vectors are increasingly used as an effective and safe approach to deliver genetic material to the central nervous system (CNS). The AAV9-derived variants, AAV-PHP. B and AAV-PHP.eB, reportedly broadly transduce cells throughout the CNS compared to the original serotype 9, AAV9. As non-human primate data are scarce, we here evaluated the CNS transduction efficiencies after lumbar intrathecal bolus delivery of identical doses of either AAV-PHP. B:CAG-EGFP or AAV-PHP. eB:CAG-EGFP in rhesus macaque monkeys. AAV-PHP.eB achieved a more efficient and widespread CNS transduction compared to AAV-PHP.B. We report a strong neuronal and oligodendroglial tropism for both variants in the putamen and in the hippocampus. This proof-of-concept experiment highlights the potential value of intrathecal infusions of AAV-PHP.eB to distribute genetic material in the CNS with cell-type specificity and introduces a new opportunity to model brain diseases in rhesus macaque monkeys and further develop gene therapies targeting the CNS in humans.

Anatomical predictors of cognitive decline after subthalamic stimulation in Parkinson's disease.

We investigated whether pre-operative MRI measures of focal brain atrophy could predict cognitive decline occurring after deep brain stimulation (DBS) of the subthalamic nucleus (STN) in patients with Parkinson's disease (PD). For that purpose, we prospectively collected data of 42 consecutive patients with PD who underwent bilateral STN-DBS. Normalized brain structure volumes and cortical thicknesses were measured on pre-operative T1-weighted MRI. Patients were tested for their cognitive performances before surgery and 1 year after. After controlling for age, gender, pre-operative disease severity, change in dopaminomimetic dose after surgery and contact location, we found correlations: (1) between the variation of the total Mattis dementia rating scale (MDRS) score and left lateral ventricle volume (p = 0.032), (2) between the variation of the initiation/perseveration subscore of the MDRS and the left nucleus accumbens volume (p = 0.042) and the left lateral ventricle volume (p = 0.017) and (3) between the variation of the backward digit-span task and the right and left superior frontal gyrus thickness (p = 0.004 and p = 0.007, respectively). Left nucleus accumbens atrophy was associated with decline in the initiation/perseveration subscore with the largest effect size (d = - 1.64). Pre-operative left nucleus accumbens volume strongly predicted postoperative decline in the initiation/attention subscore (AUC = 0.92, p < 0.001, 96.3% sensitivity, 80.0% specificity, 92.9% PPV and 92.9% NPV). We conclude that the morphometric measures of brain atrophy usually associated with cognitive impairment in PD can also explain or predict a part of cognitive decline after bilateral STN-DBS. In particular, the left accumbens nucleus volume could be considered as a promising marker for guiding surgical decisions.

Sturge-Weber syndrome with late onset hemiplegic migraine-like attacks and progressive unilateral cerebral atrophy.

BACKGROUND: Sturge-Weber syndrome (SWS) is an uncommon etiology of hemiplegic migraine-like (HM-like) attacks, associated with epilepsy and mental retardation. CASE: We report the case of a 40-year-old woman with SWS who has been suffering from HM-like episodes since she was 24, with no history of seizure or mental retardation. Susceptibility weighted imaging (SWI)-MRI and CT scans have shown bilateral calcifications of the choroidal plexuses, a developmental venous anomaly with dilated transmedullary veins and a left parieto-occipital leptomeningeal angioma. (18)F-Fluorodeoxyglucose (FDG)-PET/CT revealed a diffuse left-hemisphere hypometabolism. The comparison between the MRI performed at the age of 24 and the one performed at the age of 40 highlighted a progressive unilateral fronto-temporo-parietal atrophy. Surprisingly, even now, cognitive functions of this patient are relatively preserved. Lamotrigine permitted an improvement of HM-like attacks. DISCUSSION: Explanations for this minimally symptomatic form of SWS may be the absence of seizure, the importance of her deep venous drainage, the absence of cortical calcification and white matter impairment in the affected hemisphere, and, paradoxically, the severely asymmetric cortical metabolism. Furthermore, this case reinforces the hypothesis that alteration of cerebral hemodynamics could precipitate the cortical spreading depression giving rise to migraine with aura. CONCLUSION: We propose to consider SWS as a cause of apparently isolated hemiplegic migraine and lamotrigine as a preventive medication in HM-like attacks.