Options for Evaluating Treatment Benefit in MCI and Prodromal Alzheimer’s Disease: Content Validity of the Perceived Deficits Questionnaire (PDQ) in Patients with Early Symptoms of Cognitive Decline

Background: Many instruments used to assess outcomes of treatment for Alzheimer’s disease (AD) have no published evidence of their relevance and content validity in earlier stages of the disease, i.e., mild cognitive impairment, or prodromal AD (pAD). The objective of this project was to evaluate the applicability and usefulness of the Perceived Deficits Questionnaire (PDQ) as an outcome measure in this population using qualitative methodology to support content validity. Method: Two waves of qualitative interviews were conducted in patients with MCI and pAD. Results: Evidence for content validity and usefulness of the instrument was demonstrated in the patient interviews. Minor modifications to the wording of several items were suggested for the PDQ and the recall period was changed. Conclusion: With these modifications, the PDQ has improved content validity and relevance. It is therefore a potentially useful outcome measure to evaluate therapeutic benefit in interventional studies of patients in the early stages of AD.

Episodic Learning and Memory in Prodromal Huntington’s Disease: The Role of Multimodal Encoding and Selective Reminding

This study investigated episodic memory in prodromal HD. Three groups were compared (N = 70): mutation carriers with less than 12.5 years to disease onset (n = 16), mutation carriers with 12.5 or more years to disease onset (n = 16), and noncarriers (n = 38). Episodic memory was assessed using the Fuld Object Memory Evaluation, which included multimodal presentation and selective reminding, and the Claeson-Dahl Learning Test which included verbal repeated presentation and recall trials. Both carrier groups demonstrated deficient episodic memory compared to noncarriers. The results suggest deficient episodic memory in prodromal HD, and that inconsistent retrieval contributes to these deficits. Multimodal presentation attenuates the deficits.

The underlying mechanism of prodromal PD:insights from the parasympathetic nervous system and the olfactory system

Neurodegeneration of Parkinson’s disease(PD)starts in an insidious manner,30–50%of dopaminergic neurons have been lost in the substantia nigra before clinical diagnosis.Prodromal stage of the disease,during which the disease pathology has started but is insufficient to result in clinical manifestations,offers a valuable window for disease-modifying therapies.The most focused underlying mechanisms linking the pathological pattern and clinical characteristics of prodromal PD are the prion hypothesis of alpha-synuclein and the selective vulnerability of neurons.In this review,we consider the two potential portals,the vagus nerve and the olfactory bulb,through which abnormal alpha-synuclein can access the brain.We review the clinical,pathological and neuroimaging evidence of the parasympathetic nervous system and the olfactory system in the neurodegenerative process and using the two systems as models to discuss the internal homogeneity and heterogeneity of the prodromal stage of PD,including both the clustering and subtyping of symptoms and signs.Finally,we offer some suggestions on future directions for imaging studies in prodromal Parkinson’s disease.

Alpha-synuclein overexpression in the olfactory bulb initiates prodromal symptoms and pathology of Parkinson’s disease

Background:Parkinson’s disease(PD)is a neurodegenerative disease characterized by intraneuronal Lewy Body(LB)aggregates composed of misfolded alpha-synuclein(α-syn).The spread of misfoldedα-syn follows a typical pattern:starting in the olfactory bulb(OB)and the gut,this pathology is followed by the progressive invasion of misfoldedα-syn to the posterior part of the brain.It is unknown whether the administration of human mutant alpha-synuclein(hm-α-syn,a human mutation which occurs in familial PD)into the OB of rats would trigger similarα-syn propagation and subsequently cause pathological changes in broader brain fields associated to PD and establish an animal model of prodromal PD.Methods:hm-α-syn was overexpressed in the OB of rats with an AAV injection.Then motor and non-motor symptoms of the SD rats were tested in different behavioral tasks following the AAV injection.In follow-up studies,pathological mechanisms ofα-syn spread were explored at the histological,biochemical and micro-structure levels.Results:The experimental results indicated that hm-α-syn was overexpressed in the OB 3 weeks after the AAV injection.1)overexpression of the Hm-α-syn in the OB by the AAV injection could transfer to wider adjacent fields beyond the monosynaptic scope.2)The number of tyrosine hydroxylase positive cells body and fibers was decreased in the substantia nigra(SN)12 weeks after AAV injection.This was consistent with decreased levels of the DA neurotransmitter.Importantly,behavioral dysfunctions were found that included olfactory impairment after 3 weeks,motor ability impairment and decreased muscular coordination on a rotarod 6 weeks after the AAV injection.3)The morphological level studies found that the Golgi staining revealed the number of neuronal branches and synapses in the OB,prefrontal cortex(PFC),hippocampus(Hip)and striatum caudate putamen(CPU)were decreased.4)phosphorylatedα-syn,at Ser-129(pSer129),was found to be increased in hm-α-syn injected animals in comparison to controls that overexpressed GFP alone,which was also found in the most of LB stained by the thioflavine S(ThS)in the SN field.5)A marker of autophagy(LC3B)was increased in serval fields,which was colacolizated with a marker of apoptosis in the SN field.Conclusions:These results demonstrate that expression of exogenous mutantα-syn in the OB induces pathological changes in the sensitive brain fields by transferring pathogenicα-syn to adjacent fields.This method may be useful for establishing an animal model of prodromal PD.

Analysis of the prodromal symptoms of unexplained sudden death in patients with or without underlying diseases

Background In recent years, the incidence of unexplained sudden death has risen significantly across the world. However, it occurred suddenly, often in young apparently healthy individuals and almost 50% of the patients did not have any warning signals or symptoms. Therefore, the prodromal symptoms before the incident are extremely important for early prediction of sudden death. In this article, we aimed to explore the value of prodromal symptoms for unexplained sudden death and whether the prodromal symptoms have a predictive function to unexplained sudden death （USD） without underlying diseases. Methods A total of 208 sudden death cases were selected for the survey in the Emergency Department of Peking University Third Hospital from January 2006 to December 2009 and their medical records were reviewed. The patients were divided into two groups, 65 patients had underlying diseases while 143 had not underlying diseases. In the meantime, their prodromal symptoms were collected and compared, prodromal symptoms including chest distress, dyspnea, syncope, fever, headache, vomiting, etc. Results Patients with underlying diseases were compared to those without underlying diseases associated with sudden death; there was no significant difference in gender and age distribution. Among the 208 cases, 39 cases （18.75%） had prodromal symptoms, patients with underlying diseases had prodromal symptoms in 12 cases （18.46%）, while patients without underlying diseases had prodromal symptoms in 27 cases （18.88%）. The difference between the two groups with prodromal symptoms was not statistically significant （P 〉0.05）. Conclusions Prodromal symptoms are extremely important warning signals in the occurrence of USD. It has equally important predictive value for patients both with and without underlying diseases, especially in predicting sudden death caused by cardiopulmonary and neurological diseases.

PVSG and WHO vs European Clinical,Molecular and Pathological Criteria for prefibrotic myeloproliferative neoplasms

The Polycythemia Vera Study Group(PVSG),World Health Organization(WHO) and European Clinical,Molecular and Pathological(ECMP) classifications agree upon the diagnostic criteria for polycythemia vera(PV) and advanced primary myelofibrosis(MF). Essential thrombocythemia(ET) according to PVSG and 2007/2008 WHO criteria comprises three variants of JAK2V617 F mutated ET when the ECMP criteria are applied. These include normocellular ET,hypercellular ET with features of early PV(prodromal PV),and hypercellular ET due to megakaryocytic,granulocytic myeloprolifera-tion(ET.MGM). Evolution of prodromal PV into overt PV is common. Development of MF is rare in normocellular ET(WHO-ET) but rather common in hypercellular ET.MGM. The JAK2V617 F mutation burden in heterozygous mutated normocellular ET and in heterozygous/homozygous or homozygous mutated PV and ET.MGM is of major prognostic significance. JAK2/MPL wild type ET associated with prefibrotic primary megakaryocytic and granulocytic myeloproliferation(PMGM) is characterized by densely clustered immature dysmorphic megakaryocytes with bulky(bulbous) hyperchromatic nuclei,which are never seen in JAK2V617 F mutated ET,and PV and also not in MPL515 mutated normocellular ET(WHO-ET). JAK2V617 mutation burden,spleen size,LDH,circulating CD34+ cells,and pre-treatment bone marrow histopathology are mandatory to stage the myeloproliferative neoplasms ET,PV,PMGM for proper prognosis assessment and therapeutic implications. MF itself is not a disease because reticulin fibrosis and reticulin/collagen fibrosis are secondary responses of activated polyclonal fibroblasts to cytokines released from the clonal myeloproliferative granulocytic and megakaryocytic progenitor cells in ET.MGM,PV and PMGM.

Can population genomics guide future therapeutic gene transfer strategies for Parkinson’s disease?

Medical and surgical therapies for patients with Parkinson’s disease (PD) are typically considered and initiated upon development of clinical signs, especially therapeutic gene transfer therapies. Early clinical trials delivering transgenes within the brains of PD patients have confirmed their safety and suggested mild to moderate efficacy. Confirmatory phase III trials have yet to be undertaken with any of the current treatment regimens. During the development of PD gene therapy, mapping of the human genome was finalized and provides major insights into the normal and pathogenic genetic variabilities of populations. Genome wide association studies (GWAS) have expanded the genetic defects and risk factors accompanying clinical PD. Advanced genomic investigations may allow asymptomatic individuals with a high risk of developing PD, and evident presymptomatic nigrostriatal deficiencies, to consider early treatment approaches. Herein we propose that certain genomically and clinically defined PD patients may provide unique opportunities for testing neuronotrophic gene therapy in a pathobiological environment that is antecedent to overt motoric dysfunction. Such an approach may finally allow testing of the disease-altering capabilities of therapeutic gene transfer in PD.

Investigation of the incidences of non-mo-tor symptoms in siblings and spouses of patients withParkinson's disease

Objective Non-motor symptoms are important prodromal characteristics of Parkinson's disease(PD).The siblings and the spouses of PD patients do not have classic motor symptoms.This study aimed to investigate if they have PD prodromal symptoms.Methods A total of 98 PD patients from the Affiliated Hospital of Yangzhou University were recruited between January 2015 and August 2017;256 siblings of these patients were included in a siblings group,87 spouses of PD patients were included in a spouses group and 250 healthy individuals were included in a control group.Various scales were used to assess non-motor symptoms,including depression,anxiety,cognitive function,sleep status,constipation,daytime sleepiness,subjective olfactory disorder,rapid-eye-movement sleep behavior disorder(RBD),and restless legs syndrome(RLS).Results The incidence of anxiety(OR=3.06,95% CI 1.86-5.05,P<0.01),depression(OR=2.16,95% CI 1.16-4.04,P=0.01),RBD(OR=3.83,95% CI 1.79-8.19,P<0.01)and subjective olfactory disorder(OR=4.48,95% CI 2.02-9.90,P<0.01)was higher in the siblings group than in the control group.There were no statistically significant differences in constipation,cognitive impairment,sleep disorder,daytime sleepiness,and RLS between the two groups.There were no statistically significant differences in non-motor symptoms between the spouses group and the control group,except that the mild depression(OR=2.58,95% CI 1.07-6.20,P=0.03)in the spouses group was more obvious.Conclusion The siblings of PD patients are more likely to have PD prodromal symptoms compared with those without PD family history,perhaps because PD patients and their siblings have common pathogenic genetic factors and early living environment for neurode-generation.There are no obvious non-motor symptoms in the spouses of PD patients.It can be concluded that the onset of PD is not related to the family life environment in adulthood.