9 When the spark goes out: the neurology of apathy and motivation

Disorders of motivation are common across brain disorders. Clinicians frequently encounter pathological apathy across a range of conditions, including many neurodegenerative conditions such as small cerebrovascular disease, Parkinsons and Alzheimers disease. It is now becoming understood that apathy has a poor prognosis for long-term functional and cognitive outcome. Unfortunately, we understand very little about the mechanisms underlying the syndrome.In this talk, I shall put forward a conceptual framework with which we can begin to understand apathy by considering the processes that normally underlie motivated, goal- directed behavior. In particular Ill focus on the ability to generate options for behavior and effort-based decision making for rewards. Recent studies of the latter have been particularly revealing in both healthy people and neurological patient populations.Several lines of evidence suggest that when we make decisions about how much effort we might invest in actions, we weigh up the costs involved for the potential rewards to be obtained. Functional imaging in healthy people reveals both medial frontal and basal ganglia involvement when individuals make such decisions. In patients with apathy, this evaluation is altered. Apathetic patients show blunted sensitivity to rewards and less inclination to invest effort for low rewards than healthy individuals. Some evidence shows that these factors can be improved by dopaminergic medication. The findings support the view that it might be possible to provide a mechanistic account of the syndrome of apathy which might lead to treatments for the disorder.

SLC25A19 deficiency and bilateral striatal necrosis with polyneuropathy: a new case and review of the literature

ObjectivesBiallelic mutations in the SLC25A19 gene impair the function of the thiamine mitochondrial carrier, leading to two distinct clinical phenotypes. Homozygosity for the c.530G > C mutation is invariably associated to Amish lethal microcephaly. The second phenotype, reported only in 8 patients homozygous for different non-Amish mutations (c.373G > A, c.580T > C, c.910G > A, c.869T > A, c.576G > C), is characterized by bilateral striatal necrosis and peripheral polyneuropathy. We report a new patient with the non-Amish SLC25A19 phenotype showing compound heterozygosity for the new variant c.673G > A and the known mutation c.373G > A.Case presentationThe natural history of non-Amish SLC25A19 deficiency is characterized by acute episodes of fever-induced encephalopathy accompanied by isolated lactic acidosis and Leigh-like features at magnetic resonance imaging (MRI). Acute episodes are prevented by high-dose thiamine treatment (600 mg/day). As shown in the new case, both mild clinical signs and basal ganglia involvement can precede the acute encephalopathic onset of the disease, potentially allowing treatment anticipation and prevention of acute brain damage. Peripheral axonal neuropathy, observed in 7 out of 9 patients, is not improved by thiamine therapy. In two early treated patients, however, peripheral neuropathy did not occur even on long-term follow-up, suggesting a potential preventive role of treatment anticipation also at the peripheral level.ConclusionsNon-Amish SLC25A19 deficiency is an extra-rare cause of Leigh syndrome responsive to thiamine treatment. Ex adiuvantibus thiamine treatment is mandatory in any patient with Leigh-like features.

MINPP1 prevents intracellular accumulation of the cation chelator inositol hexakisphosphate and is mutated in Pontocerebellar Hypoplasia

ABSTRACTInositol polyphosphates are vital metabolic and secondary messengers, involved in diverse cellular functions. Therefore, tight regulation of inositol polyphosphate metabolism is essential for proper cell physiology. Here, we describe an early-onset neurodegenerative syndrome caused by loss-of-function mutations in the multiple inositol polyphosphate phosphatase 1 gene (MINPP1). Patients were found to have a distinct type of Pontocerebellar Hypoplasia with typical basal ganglia involvement on neuroimaging. We found that patient-derived and genome edited MINPP1-/- induced pluripotent stem cells (iPSCs) are not able to differentiate efficiently into neurons. MINPP1 deficiency results in an intracellular imbalance of the inositol polyphosphate metabolism. This metabolic defect is characterized by an accumulation of highly phosphorylated inositols, mostly inositol hexakiphosphate (IP6), detected in HEK293, fibroblasts, iPSCs and differentiating neurons lacking MINPP1. In mutant cells, higher IP6 level is expected to be associated with an increased chelation of intracellular cations, such as iron or calcium, resulting in decreased levels of available ions. These data suggest the involvement of IP6-mediated chelation on Pontocerebellar Hypoplasia disease pathology and thereby highlight the critical role of MINPP1 in the regulation of human brain development and homeostasis.

Neuromyelitis optica spectrum disorder with massive basal ganglia involvement: a case report

Background Occurrence of basal ganglia involvement in neuromyelitis optica spectrum disorders (NMOSD) has rarely been reported and none documented pathologically. Case presentation A 73-year-old female was clinically diagnosed with a NMOSD based on the clinical and radiological features and positive serum autoantibodies to AQP4. One month before her death, she became acutely ill with disturbed consciousness and right hemiparesis, and was diagnosed and treated as having basal ganglia infarction based on the brain CT. She made a partial recovery but later died from heart failure. At autopsy, the corresponding basal ganglia process revealed a large fresh area of necrosis. Histologically, several pathological signatures of NMOSD could be recognized in the lesion, including inflammatory cell infiltrations by B and T lymphocytes, perivascular complement and fibrinogen deposition, and the appearance of numerous phagocytosed corpora amylacea within the infiltrating macrophages. Conclusions The present case illustrates that basal ganglia may be directly involved in the pathological processes of NMOSD, although the possibility of modification of the lesions by superimposed regional ischemia could not be excluded.