Alzheimer's disease and other related neurodegenerative diseases are highly debilitating disorders that affect millions of people worldwide. Efforts towards developing effective treatments for these disorders have shown limited efficacy at best, with no true cure to this day being present. Recent work, both clinical and experimental, indicates that many neurodegenerative disorders often display a coexisting metabolic dysfunction which may exacerbate neurological symptoms. It stands to reason therefore that metabolic pathways may themselves contain promising therapeutic targets for major neurodegenerative diseases. In this review, we provide an overview of some of the most recent evidence for metabolic dysregulation in Alzheimer's disease, Huntington's disease, and Parkinson's disease, and discuss several potential mechanisms that may underlie the potential relationships between metabolic dysfunction and etiology of nervous system degeneration. We also highlight some prominent signaling pathways involved in the link between peripheral metabolism and the central nervous system that are potential targets for future therapies, and we will review some of the clinical progress in this field. It is likely that in the near future, therapeutics with combinatorial neuroprotective and 'eumetabolic' activities may possess superior efficacies compared to less pluripotent remedies.

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Metabolic Dysfunction in Alzheimer’s Disease and Related Neurodegenerative Disorders

[Huntington's disease].

It is generally believed that treatments are available to manage irritability in Huntington's disease (HD). However, lack of an evidence base prevents the establishment of treatment guidelines for this symptom. The research literature fails to address behavioral intervention strategies, drug selection, drug dosing, management of inadequate response to a single drug, or preferred drugs when additional behavioral symptoms comorbid to irritability are present. In an effort to inform clinical decision-making we surveyed an international group of experts to address these points. The experts consistently endorsed an antipsychotic drug (APD) as first choice for treatment of urgent and aggressive irritability behaviors. However, there was variation in practice patterns for treating less severe symptoms. Serotonin reuptake inhibitors (SSRIs) were first choice drug treatments by most respondents across all geographic regions. However, APDs were also endorsed as first choice for mild or moderate irritability, more frequently in Europe than in North America and Australia. Antiepileptic mood stabilizers (AEDs) were used by fewer respondents as first choice drug. Perceived efficacy for control of mild or moderate irritability was judged somewhat higher for APDs than SSRIs or AEDs. Benzodiazepines were not used as monotherapy, but frequently as an adjunctive drug in the setting of comorbid anxiety. Though many cited lack of experience with mirtazapine, others familiar with its use in HD chose it as an alternative monotherapy, or as adjunctive therapy if insomnia was a comorbid factor. This report presents survey results, reviews available irritability studies, and lastly proposes an algorithm for the treatment of irritability in HD derived from expert preferences obtained through this survey.

An International Survey-based Algorithm for the Pharmacologic Treatment of Irritability in Huntington's Disease.

In the past decade, a number of genetic causes of parkinsonism have been identified. As a consequence, clinicians have to consider an increasing range of differential diagnoses when confronted with a patient with parkinsonism with a positive family history. While well-established monogenic forms with PARK acronyms have been reviewed extensively, less emphasis has been placed on other inherited conditions that may also present with signs of parkinsonism or even mimic idiopathic Parkinson's disease clinically. In this review, we focus on three different scenarios in patients with an overall early age of onset of parkinsonism: (i) atypical features in patients with mutations in one of the "PARK" genes; (ii) classical parkinsonism due to mutations in "other than-PARK" genes or yet other genes where parkinsonism may be a well-recognized, concomitant, or even an isolated feature; (iii) atypical parkinsonism in other genetic disorders which are, however, typically characterized by features other than parkinsonism. Atypical features in patients from Group I include, for example, a slower disease course (PARK2, PARK6, PARK7) or dementia (PARK1/4, PARK14). Conditions in Group II have been designated by a DYT or SCA acronym (for example, DYT5 or SCA3) and also include patients with heterozygous GBA mutations, mitochondrial gene mutations. Group III comprises mutations in the FMR1, MAPT, GRN, ATP7B, PANK2, FBXO7, CHAC, FTL1, Huntingtin, JPH3 genes, and a number of even rarer, miscellaneous conditions.

Hereditary parkinsonism: Parkinson disease look-alikes--an algorithm for clinicians to "PARK" genes and beyond.

CAG repeat lengths ≥335 attenuate the phenotype in the R6/2 Huntington’s disease transgenic mouse

Huntington disease is a dominantly inherited, neurodegenerative disorder, usually with onset in the fourth to fifth decade of life but in a small proportion of patients before the age of 20 years. The early-onset form, juvenile Huntington disease, is clinically different from that of more common adult-onset forms and includes cognitive decline, parkinsonism, myoclonus, and seizures. We report a case of a boy with juvenile Huntington disease with a very early age at disease onset (3 years). The suspected clinical diagnosis was confirmed by DNA analysis, which revealed (CAG)(n) expansion into the range characteristic of juvenile Huntington disease (95 repeats). The clinical course of the disease was typical for the juvenile form of Huntington disease, but the diagnosis was not so obvious because there was no history of any neurodegenerative disorder in the family. The child died at the age of 11 years. The detailed neuropathologic investigations performed postmortem showed the characteristic features of Huntington disease. As the patient's de novo mutation was very unlikely to occur, genetic counseling and the possibility of predictive testing were proposed to the family. Indirect molecular data indicate the familial character of the disease, with strong anticipation of transmission.

Dorota Hoffman-Zacharska

Papers

Huntington disease in a 9-year-old boy: clinical course and neuropathologic examination.