Is Low Psychomotor Speed a Marker of Brain Vulnerability in Late Life? Digit Symbol Substitution Test in the Prediction of Alzheimer, Parkinson, Stroke, Disability, and Depression.

BACKGROUND: Dementia, stroke, depression, and disability are frequent in late life and are major causes of quality of life disruption and family burden. Even though each of these disorders relies on specific pathogenic processes, a common clinical manifestation is psychomotor slowing. OBJECTIVE: We assessed the relevance of a simple marker of low psychomotor speed in predicting several brain outcomes: dementia, Alzheimer's disease (AD), Parkinson's disease (PD), stroke, depressive symptoms, and disability in activities of daily living (ADL) and instrumental ADL (IADL). METHODS: PAQUID is a population-based study involving 3,777 individuals aged 65 or older prospectively followed-up with repeated clinical evaluations. After 10 years, 437 participants developed dementia, 333 developed AD, 71 developed PD, 207 reported incident stroke, 404 developed disability in ADL, 994 in IADL, and 494 developed depressive symptomology. Psychomotor speed was measured with the digit symbol substitution test (DSST). Cox proportional hazards models controlled for several confounders assessed the risk of incident outcomes. RESULTS: Participants with low DSST performance had increased risk of incident all-type dementia (hazard ratio [HR] 3.41, p < 0.0001) and AD-type dementia (HR 3.18, p < 0.0001). Higher risk for PD (HR 2.98, p = 0.04), IADL (HR 1.82, p < 0.0001), ADL disability (HR 1.95, p = 0.001), depressive symptoms (HR 1.53, p = 0.03), and a statistical trend for stroke (HR 1.88, p = 0.09) was also found. CONCLUSION: Low psychomotor speed is associated with an increased risk of developing various brain outcomes: dementia, AD, PD, disability, depressive symptoms, and marginally stroke. Low psychomotor speed may be the consequence of a number of discrete cerebral abnormalities and could be considered as a marker of brain vulnerability. In clinical practice, a low score in DSST should be seen as a warning sign of possible negative evolution.

Repeated Mild Concussive Events Heighten the Vulnerability of Brain to Blast Exposure.

Mild concussive events without loss of consciousness are typically left untreated and can result in neurological abnormalities at later stages of life. No systematic studies have been carried out to determine the effect of concussion or repeated mild concussive episodes on brain vulnerability towards blast exposure. We have evaluated the effect of repeated mild concussive events on the vulnerability of brain to blast exposure using neurobehavioral functional assessments. Rats were subjected to either repeated mild concussive impacts (two impacts 1 week apart using a modified Marmarou weight drop model), a single blast exposure (19 psi using an advanced blast simulator), or a single blast exposure one day after the second mild concussive impact. Neurobehavioral changes were monitored using rotating pole test, open field exploration test, and novel object recognition test. Rotating pole test results indicated that vestibulomotor function was unaffected by blast or repeated mild concussive impacts, but significant impairment was observed in the blast exposed animals who had prior repeated mild concussive impacts. Novel object recognition test revealed short-term memory loss at 1 month post-blast only in rats subjected to both repeated mild concussive impacts and blast. Horizontal activity count, ambulatory activity count, center time and margin time legacies in the open field exploratory activity test indicated that only those rats exposed to both repeated mild concussive impacts and blast develop anxiety-like behaviors at both acute and sub-acute time-points. The results indicate that a history of repeated mild concussive episodes heightens brain vulnerability to blast exposure.

Brain growth until adolescence after a neonatal focal injury: sex related differences beyond lesion effect.

Introduction: Early focal brain injuries lead to long-term disabilities with frequent cognitive impairments, suggesting global dysfunction beyond the lesion. While plasticity of the immature brain promotes better learning, outcome variability across individuals is multifactorial. Males are more vulnerable to early injuries and neurodevelopmental disorders than females, but long-term sex differences in brain growth after an early focal lesion have not been described yet. With this MRI longitudinal morphometry study of brain development after a Neonatal Arterial Ischemic Stroke (NAIS), we searched for differences between males and females in the trajectories of ipsi- and contralesional gray matter growth in childhood and adolescence, while accounting for lesion characteristics. Methods: We relied on a longitudinal cohort (AVCnn) of patients with unilateral NAIS who underwent clinical and MRI assessments at ages 7 and 16 were compared to age-matched controls. Non-lesioned volumes of gray matter (hemispheres, lobes, regions, deep structures, cerebellum) were extracted from segmented T1 MRI images at 7 (Patients: 23 M, 16 F; Controls: 17 M, 18 F) and 16 (Patients: 18 M, 11 F; Controls: 16 M, 15 F). These volumes were analyzed using a Linear Mixed Model accounting for age, sex, and lesion characteristics. Results: Whole hemisphere volumes were reduced at both ages in patients compared to controls (gray matter volume: -16% in males, -10% in females). In ipsilesional hemisphere, cortical gray matter and thalamic volume losses (average -13%) mostly depended on lesion severity, suggesting diaschisis, with minimal effect of patient sex. In the contralesional hemisphere however, we consistently found sex differences in gray matter volumes, as only male volumes were smaller than in male controls (average -7.5%), mostly in territories mirroring the contralateral lesion. Females did not significantly deviate from the typical trajectories of female controls. Similar sex differences were found in both cerebellar hemispheres. Discussion: These results suggest sex-dependent growth trajectories after an early brain lesion with a contralesional growth deficit in males only. The similarity of patterns at ages 7 and 16 suggests that puberty has little effect on these trajectories, and that most of the deviation in males occurs in early childhood, in line with the well-described perinatal vulnerability of the male brain, and with no compensation thereafter.

Brain vulnerability to chemotherapy toxicities.

Chemotherapy-induced cognitive changes have been an increasing concern among cancer survivors. By using adjuvant treatment for breast cancer as the prototype, this manuscript reviews research from neuropsychological, imaging, genetic, and animal model studies that have examined the clinical presentation and potential mechanisms for cognitive changes associated with exposure to chemotherapy. An impressive body of research supports the hypothesis that a subgroup of patients is vulnerable to post-treatment cognitive changes, although not exclusively related to chemotherapy. Further, imaging and animal model studies provide accumulating evidence of putative mechanisms for chemotherapy-induced cognitive change. Models of aging are also reviewed in support of the proposal that cognitive changes associated with cancer and cancer treatments can be viewed in the context of factors that affect the trajectory of normal aging.

Excessive White Matter Hyperintensity Increases Susceptibility to Poor Functional Outcomes After Acute Ischemic Stroke.

Objective: To personalize the prognostication of post-stroke outcome using MRI-detected cerebrovascular pathology, we sought to investigate the association between the excessive white matter hyperintensity (WMH) burden unaccounted for by the traditional stroke risk profile of individual patients and their long-term functional outcomes after a stroke. Methods: We included 890 patients who survived after an acute ischemic stroke from the MRI-Genetics Interface Exploration (MRI-GENIE) study, for whom data on vascular risk factors (VRFs), including age, sex, atrial fibrillation, diabetes mellitus, hypertension, coronary artery disease, smoking, prior stroke history, as well as acute stroke severity, 3- to-6-month modified Rankin Scale score (mRS), WMH, and brain volumes, were available. We defined the unaccounted WMH (uWMH) burden via modeling of expected WMH burden based on the VRF profile of each individual patient. The association of uWMH and mRS score was analyzed by linear regression analysis. The odds ratios of patients who achieved full functional independence (mRS < 2) in between trichotomized uWMH burden groups were calculated by pair-wise comparisons. Results: The expected WMH volume was estimated with respect to known VRFs. The uWMH burden was associated with a long-term functional outcome (ß = 0.104, p < 0.01). Excessive uWMH burden significantly reduced the odds of achieving full functional independence after a stroke compared to the low and average uWMH burden [OR = 0.4, 95% CI: (0.25, 0.63), p < 0.01 and OR = 0.61, 95% CI: (0.42, 0.87), p < 0.01, respectively]. Conclusion: The excessive amount of uWMH burden unaccounted for by the traditional VRF profile was associated with worse post-stroke functional outcomes. Further studies are needed to evaluate a lifetime brain injury reflected in WMH unrelated to the VRF profile of a patient as an important factor for stroke recovery and a plausible indicator of brain health.

The vulnerability of the immature brain.

The concept of vulnerability of the immature brain is multifactorial by definition. Newer scientific work in this area has shifted and enlarged the concept from theoretical frameworks to the multiple levels (molecular, cellular, anatomic, network, behavioral) of the organization of the growing brain. The concept of vulnerability was first introduced by Donald O. Hebb in the 1950s and referred to the inability of the immature brain to completely recover normal development after a brain insult. The concept of vulnerability was further extended to the limitations of the brain in the development of specific skills in neuronal substrates originally used for other functions. We present an overview of some neurodevelopmental processes that characterize the immature brain and that can predict vulnerability in the case of disturbances: Hebb's principle, synaptic homeostasis, selective vulnerability of immature cells in mammals, and inherited constraint networks. A better understanding of the vulnerability mechanisms may help in early detection and prevention and further proposed individualized therapeutic approaches to enhance children's developmental outcomes.

Untreated PKU Patients without Intellectual Disability: What Do They Teach Us?

Phenylketonuria (PKU) management is aimed at preventing neurocognitive and psychosocial dysfunction by keeping plasma phenylalanine concentrations within the recommended target range. It can be questioned, however, whether universal plasma phenylalanine target levels would result in optimal neurocognitive outcomes for all patients, as similar plasma phenylalanine concentrations do not seem to have the same consequences to the brain for each PKU individual. To better understand the inter-individual differences in brain vulnerability to high plasma phenylalanine concentrations, we aimed to identify untreated and/or late-diagnosed PKU patients with near-normal outcome, despite high plasma phenylalanine concentrations, who are still alive. In total, we identified 16 such cases. While intellectual functioning in these patients was relatively unaffected, they often did present other neurological, psychological, and behavioral problems. Thereby, these "unusual" PKU patients show that the classical symptomatology of untreated or late-treated PKU may have to be rewritten. Moreover, these cases show that a lack of intellectual dysfunction despite high plasma phenylalanine concentrations does not necessarily imply that these high phenylalanine concentrations have not been toxic to the brain. Also, these cases may suggest that different mechanisms are involved in PKU pathophysiology, of which the relative importance seems to differ between patients and possibly also with increasing age. Further research should aim to better distinguish PKU patients with respect to their cerebral effects to high plasma phenylalanine concentrations.

Can untreated PKU patients escape from intellectual disability? A systematic review.

BACKGROUND: Phenylketonuria (PKU) is often considered as the classical example of a genetic disorder in which severe symptoms can nowadays successfully be prevented by early diagnosis and treatment. In contrast, untreated or late-treated PKU is known to result in severe intellectual disability, seizures, and behavioral disturbances. Rarely, however, untreated or late-diagnosed PKU patients with high plasma phenylalanine concentrations have been reported to escape from intellectual disability. The present study aimed to review published cases of such PKU patients. METHODS: To this purpose, we conducted a literature search in PubMed and EMBASE up to 8th of September 2017 to identify cases with 1) PKU diagnosis and start of treatment after 7 years of age; 2) untreated plasma phenylalanine concentrations ≥1200 µmol/l; and 3) IQ ≥80. Literature search, checking reference lists, selection of articles, and extraction of data were performed by two independent researchers. RESULTS: In total, we identified 59 published cases of patients with late-diagnosed PKU and unexpected favorable outcome who met the inclusion criteria. Although all investigated patients had intellectual functioning within the normal range, at least 19 showed other neurological, psychological, and/or behavioral symptoms. CONCLUSIONS: Based on the present findings, the classical symptomatology of untreated or late-treated PKU may need to be rewritten, not only in the sense that intellectual dysfunction is not obligatory, but also in the sense that intellectual functioning does not (re)present the full picture of brain damage due to high plasma phenylalanine concentrations. Further identification of such patients and additional analyses are necessary to better understand these differences between PKU patients.