Alzheimer's disease as a polygenic disease

Recent advances in molecular genetics have enabled the identification of the causative genes for early-onset familial Alzheimer's disease (AD). However, sporadic and late-onset familial AD, the most common forms of AD, are considered to be polygenic disorders. The presence of APOE4, one of the specific alleles of the apolipoprotein E gene, has been established as a major genetic risk factor for the development of AD. Additional risk factors are under active investigation. Such new approaches are expected to establish preventive measures or treatments for AD.     

Cerebellitis as a neurosurgical disease in pediatrics

The diagnostic evaluation and role of neurosurgery in the treatment of cerebellitis is unclear. We explore the diagnostic evaluation and subsequent role of neurosurgical intervention in pediatric cerebellitis in a case series, highlighting the diagnostic work up and treatments applied. A retrospective review was conducted of all pediatric patients diagnosed with cerebellitis for whom neurosurgery was consulted at a single center from June 2008 to February 2019. Nine patients, four males (44.4%) and five females (55.6%) were identified. Common presenting symptoms were headache (n = 6, 66.7%), emesis (n = 5, 55.6%), and altered mental status (n = 4, 44.4%). Six (66.7%) had associated infections. Imaging abnormalities included tonsillar ectopia (n = 8, 88.9%), bilateral cerebellar T2 hyperintensity (n = 6, 66.7%), and obstructive hydrocephalus (n = 6, 66.7%). Management included antibiotics, antivirals, corticosteroids, mannitol, and hypertonic saline. Four (44.4%) required external ventricular drain (EVD) placement for a mean 11 days (SD 6.8, range 4–20) for hydrocephalus; none required additional neurosurgical interventions. Seven patients (77.8%) required ICU care for a mean 11.7 days (SD 14.0 range 1–42). At follow-up (mean 20.8 months, SD 28.7, range 0.6–64.9), two patients (n = 2, 22.2%) recovered completely, and six (66.7%) were functionally dependent (mRS > 2); the most common residual deficit was cognitive impairment (n = 5, 55.6%). Neurosurgical consultation should be considered in pediatric patients with cerebellitis. In our experience, temporary CSF diversion via an EVD is employed nearly half of the time. The presence of hydrocephalus requiring neurosurgical intervention may be a predictor of severe disease and poor outcome.     

Schizophrenia as a dynamical disease

It is demonstrated that schizophrenia is a dynamical disease, i. e. that important aspects of schizophrenia can be understood on the basis of concepts of the theory of nonlinear dynamical systems. In particular, the gradual shift of a single parameter may result in completely different kinds of behavior of the entire system just like water can be in three qualitatively different states depending on the single parameter temperature. Transitions between these different states are called bifurcations or phase transitions. In case of schizophrenia the parameter may be the neurotransmitter dopamine (or serotonin or glutamate). With a high level of dopamine transmission the symptoms of schizophrenia appear, and with rather low levels those of Morbus Parkinson. In between a healthy state prevails. With respect to neuronal activity the effects of dopamine are demonstrated by a mathematical model which can be interpreted in two ways: on the one hand as a model of typical excitatory-inhibitory circuits in the cortex, on the other hand of a negative feedback loop between thalamus, prefrontal cortex and striatum. The model exhibits different types of firing patterns and their bifurcation, from various kinds of periodicities up to erratic or chaotic behavior, corresponding to different levels of dopamine concentration.     

Genetically confirmed Huntington's disease masquerading as motor neuron disease

We describe a patient with Huntington's disease (HD) who showed asymmetrical upper limb amyotrophy as a main manifestation. Chorea and psychiatric symptoms were not prominent. Electromyography revealed generalized active and chronic denervation and fasciculations. A genetic test showed 46 CAG repeats in the huntingtin gene. Asymmetrical amyotrophy restricted to the upper limb has been reported in some patients with progressive chorea and amyotrophy without acanthocytosis, but genetically proven cases of HD have rarely been reported. It is not known why only a few HD patients show the motor neuronal loss; however, certain as‐yet‐unidentified genetic factors combined with some environment factors and the underlying cellular dysfunctions by polyglutamine aggregation could be responsible for the motor neuronal loss similar to that in amyotrophic lateral sclerosis. © 2008 Movement Disorder Society     

Disruptive behavior as a predictor in Alzheimer disease

BACKGROUND: Disruptive behavior is common in Alzheimer disease (AD). There are conflicting reports regarding its ability to predict cognitive decline, functional decline, institutionalization, and mortality. OBJECTIVE: To examine whether the presence of disruptive behavior has predictive value for important outcomes in AD. DESIGN: Using the Columbia University Scale for Psychopathology in Alzheimer Disease (administered every 6 months, for a total of 3438 visit-assessments and an average of 6.9 per patient), the presence of disruptive behavior (wandering, verbal outbursts, physical threats/violence, agitation/restlessness, and sundowning) was extracted and examined as a time-dependent predictor in Cox models. The models controlled for the recruitment cohort, recruitment center, informant status, sex, age, education, a comorbidity index, baseline cognitive and functional performance, and neuroleptic use. SETTING: Five university-based AD centers in the United States and Europe (Predictors Study). PARTICIPANTS: Four hundred ninety-seven patients with early-stage AD (mean Folstein Mini-Mental State Examination score, 20 of 30 at entry) who were recruited and who underwent semiannual follow-up for as long as 14 (mean, 4.4) years. MAIN OUTCOME MEASURES: Cognitive (Columbia Mini-Mental State Examination score, < or = 20 of 57 [approximate Folstein Mini-Mental State Examination score, < or = 10 of 30]) and functional (Blessed Dementia Rating Scale score, parts I and II, > or = 10) ratings, institutionalization equivalent index, and death. RESULTS: At least 1 disruptive behavioral symptom was noted in 48% of patients at baseline and in 83% at any evaluation. Their presence was associated with increased risks of cognitive decline (hazard ratio 1.45 [95% confidence interval (CI), 1.03-2.03]), functional decline (1.66 [95% CI, 1.17-2.36]), and institutionalization (1.47 [95% CI, 1.10-1.97]). Sundowning was associated with faster cognitive decline, wandering with faster functional decline and institutionalization, and agitation/restlessness with faster cognitive and functional decline. There was no association between disruptive behavior and mortality (hazard ratio, 0.94 [95% CI, 0.71-1.25]). CONCLUSION: Disruptive behavior is very common in AD and predicts cognitive decline, functional decline, and institutionalization but not mortality.     

Amyloid-degrading enzymes as therapeutic targets in Alzheimer's disease

The steady state concentration of the Alzheimer's amyloid-beta peptide in the brain represents a balance between its biosynthesis from the transmembrane amyloid precursor protein (APP), its oligomerisation into neurotoxic and stable species and its degradation by a variety of amyloid-degrading enzymes, principally metallopeptidases. These include, among others, neprilysin (NEP) and its homologue endothelin-converting enzyme (ECE), insulysin (IDE), angiotensin-converting enzyme (ACE) and matrix metalloproteinase-9 (MMP-9). In addition, the serine proteinase, plasmin, may participate in extracellular metabolism of the amyloid peptide under regulation of the plasminogen-activator inhibitor. These various amyloid-degrading enzymes have distinct subcellular localizations, and differential responses to aging, oxidative stress and pharmacological agents and their upregulation may provide a novel and viable therapeutic strategy for prevention and treatment of Alzheimer's disease. Potential approaches to manipulate expression levels of the key amyloid-degrading enzymes are highlighted.     

NO chimeras as therapeutic agents in Alzheimer's disease

NO is an important messenger molecule in the brain, playing an important role in learning and memory, in particular via the ERK/CREB signaling pathway. NO is also a neuroprotective agent; multiple mechanisms having been demonstrated that can contribute to cell survival as levels of antioxidants and trophic factors are reduced with aging. Small molecules that mimic the biological activity of NO, including NO donors, may thus ameliorate cognition and provide neuroprotection. Several lines of evidence have linked the neurodegeneration and dementia characteristic of Alzheimer's disease with the action of beta-amyloid protein at the alpha7-nicotinic acetylcholine receptor. The interplay of Abeta with alpha7-nicotinic ACh receptors operating via the ERK signaling cascade links the amyloid cascade and the cholinergic hypothesis in pathways that impact synaptic plasticity and memory. This interplay also provides linkages to disruption of NO/cGMP signaling in AD, and in addition, recent direct evidence has been found demonstrating that Abeta downregulates the NO/cGMP/CREB pathway. Activation of soluble guanylyl cyclase elevating cGMP in the brain represents the central element of a therapeutic approach to the treatment of AD and other neurodegenerative diseases, furthermore, evidence suggests that NO may display cGMP-independent activity and may operate via multiple biochemical signaling pathways to ensure the survival of neurons subjected to stress. GT 1061 is an NO chimera, an NO mimetic compound that contains an ancillary, synergistic pharmacophore, currently in clinical trials for Alzheimer's. NO chimeras and hybrid nitrates hold promise as therapeutics for AD with multiple sites of action.