Spinocerebellar ataxia type 3 (SCA3), caused by a CAG repeat expansion in the ataxin-3 gene (ATXN3), is characterized by neuronal polyglutamine (polyQ) ATXN3 protein aggregates. Although there is no cure for SCA3, gene-silencing approaches to reduce toxic polyQ ATXN3 showed promise in preclinical models. However, a major limitation in translating putative treatments for this rare disease to the clinic is the lack of pharmacodynamic markers for use in clinical trials. Here, we developed an immunoassay that readily detects polyQ ATXN3 proteins in human biological fluids and discriminates patients with SCA3 from healthy controls and individuals with other ataxias. We show that polyQ ATXN3 serves as a marker of target engagement in human fibroblasts, which may bode well for its use in clinical trials. Last, we identified a single-nucleotide polymorphism that strongly associates with the expanded allele, thus providing an exciting drug target to abrogate detrimental events initiated by mutant ATXN3. Gene-silencing strategies for several repeat diseases are well under way, and our results are expected to improve clinical trial preparedness for SCA3 therapies.

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ObjectiveTo evaluate the pattern and severity of autonomic dysfunction in autopsy-confirmed progressive supranuclear palsy (PSP) compared to α-synuclein pathology.MethodsAutopsy-confirmed cases of 14 patients with PSP, 18 with multiple system atrophy (MSA), and 24 with Lewy body disease (LBD) with antemortem autonomic testing were reviewed retrospectively. All patients underwent comprehensive clinical evaluations by a movement disorder specialist, formal autonomic testing, and postmortem examinations at Mayo Clinic.ResultsThe absence of orthostatic hypotension (OH) was the strongest autonomic parameter that distinguished PSP from α-synucleinopathies (0% vs 69%, p < 0.0001). Tests of adrenergic failure, which distinguish neurogenic OH, also differentiated PSP from other groups. These included the pressure recovery time (p = 0.0008), adrenergic impairment score (p = 0.001), and magnitude of change of systolic (p = 0.0002) and diastolic (p = 0.0001) blood pressures (BPs) during upright tilt. In addition, REM sleep behavior disorder was seen less frequently (p = 0.006) in PSP (33%) compared to MSA (87%) and LBD (90%). Antemortem clinical diagnostic accuracy for these phenotypically variable disorders was 57% for PSP and 83% for α-synucleinopathies.ConclusionOur results suggest that the cardiovascular adrenergic system, which sustains BP during standing, is relatively unaffected, if not spared, in PSP. These findings increase our understanding of the clinical signature of PSP and have the potential to improve diagnostic accuracy in atypical parkinsonisms by distinguishing PSP from the α-synucleinopathies.

Introduction:We examined the temporal sequence of the core features in probable dementia with Lewy bodies (DLB). Methods:In 488 patients with probable DLB, the onset of each core feature and time to diagnosis was determined for men and women, and a pathologic subgroup (n = 209).Results: REM sleep behavior disorder (RBD) developed before the other core features in men and women. Men were more likely to have RBD and were diagnosed with probable DLB earlier than women. Visual hallucinations developed after the other core features in men, but in women, they appeared earlier and concurrently with fluctuations and parkinsonism. Women were older and more cognitively impaired at first visit, were less likely to have RBD, more likely to be diagnosed with probable DLB later than men, and more likely to have neocortical tangles.Discussion: An earlier latency to probable DLB was associated with men, RBD, and Lewy body disease without neocortical tangles.

Neurons in many brain regions release endocannabinoids from their dendrites that act as retrograde signals to transiently suppress neurotransmitter release from presynaptic terminals. Little is known however about the physiological mechanisms of short-term endocannabinoid-mediated plasticity under physiological conditions. Here we investigate calcium-dependent endocannabinoid release from cartwheel cells (CWCs) of the mouse dorsal cochlear nucleus (DCN) in the auditory brainstem that provide feedforward inhibition onto DCN principal neurons. We report that sustained action potential firing by CWCs evokes endocannabinoid release in response to submicromolar elevation of dendritic calcium that transiently suppresses their parallel fiber inputs by >70%. Basal spontaneous CWC firing rates are insufficient to evoke tonic suppression of PF synapses. However, elevating CWC firing rates by stimulation of parallel fibers triggers release of endocannabinoids and heterosynaptic suppression of PF inputs. Spike-evoked suppression by endocannabinoids selectively suppresses excitatory synapses but glycinergic/GABAergic inputs onto CWCs are not affected. Our findings demonstrate a mechanism of transient plasticity mediated by endocannabinoids that heterosynaptically suppresses subsets of excitatory presynaptic inputs to CWCs that regulates feedforward inhibition of DCN principal neurons and may thereby influence the output of the DCN.

Advances in the treatment and prevention of disease have contributed to an aging global population. Subsequently, there is an increasing prevalence of age‑related conditions, such as dementia. There are currently no disease‑modifying therapies commercially available, and there is a growing emphasis on strategies to prevent dementia. We have reviewed the relevant literature pertaining to dementia risk and putative prevention factors. We present our findings by summarizing the pertinent items that may play a role in prevention and conclude our recommendations at this time.

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Adult-onset leukoencephalopathy with spheroids and pigmented glia (ALSP) is the collective disease referring to patients previously diagnosed with hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) or pigmented orthochromatic leukodystrophy (POLD). ALSP is a white matter disease with a complex neurological phenotype consisting of pyramidal tract dysfunction, parkinsonism, and frontal-predominant cognitive impairment. 1 This autosomal-dominant disease typically affects females earlier than males with symptom onset in the fourth decade of life and average disease duration of 7 years. 2 In 2011, a mutation in the colonystimulating factor 1 receptor (CSF1R) gene was first identified in the initial collection of HDLS families. 3 Two separate POLD families were later found to carry CSF1R mutations, therefore confirming that HDLS and POLD were actually a single CSF1Rrelated leukoencephalopathy. 1 There are now more than 70 different pathogenic mutations, most of which occur in the tyrosine kinase domain resulting in disruption of protein function. 4 The disease is currently known as CSF1R-related leukoencephalopathy to distinguish it from a somewhat similar condition produced by mutations in the AARS2 gene 5 or other unknown genetic causes. For the genetic or sporadic cases of unknown cause, the nomenclature of ALSPgene negative seems to be appropriate for now. The CSF-1R protein is mainly expressed in microglia leading to the disease designation of microgliopathy. Recent studies from a mouse model of ALSP strongly support this designation. 6