The diagnosis of young-onset dementia

“Dementia is a major public health concern that is a growing burden owing to an ageing society. However, the high prevalence of dementia in the elderly can overshadow the importance of its occurrence in younger patients. Young-onset dementias can present a substantial diagnostic challenge but can also provide important biological insights that might also be applicable to the more common presentation in older patients. For example, the high prevalence of inherited dementias in younger age-groups has led to the identification of causative genes and subsequent molecular pathology of direct relevance to the more common sporadic disease seen in older patients. The prospect of future treatments targeted at the specific molecular pathological changes of the different dementias makes precise diagnosis essential. In this Review, we discuss the differences between young onset and late onset for the four major dementia diseases: Alzheimer’s disease, vascular disease, frontotemporal lobar degeneration (FTLD), and dementia with Lewy bodies. We also suggest a structured approach to the choice of investigations, building on the “dementia plus” concept; this concept exploits the fact that many of the diseases that cause dementia in young adults also cause additional neurological or systemic features, and the identification of these features can aid diagnosis. A diagnosis of dementia often attracts therapeutic nihilism and so we also include examples of treatable dementias that commonly present to young-onset dementia clinics.”

Lancet Neurol. 2010 Aug;9(8):793-806. doi: 10.1016/S1474-4422(10)70159-9.
The diagnosis of young-onset dementia.
Rossor MN1, Fox NC, Mummery CJ, Schott JM, Warren JD.

Cryo-EM study of tau filaments

“Alzheimer’s disease is the most common neurodegenerative disease, and there are no mechanism-based therapies. The disease is defined by the presence of abundant neurofibrillary lesions and neuritic plaques in the cerebral cortex. Neurofibrillary lesions comprise paired helical and straight tau filaments, whereas tau filaments with different morphologies characterize other neurodegenerative diseases. No high-resolution structures of tau filaments are available. Here we present cryo-electron microscopy (cryo-EM) maps at 3.4–3.5 Å resolution and corresponding atomic models of paired helical and straight filaments from the brain of an individual with Alzheimer’s disease. Filament cores are made of two identical protofilaments comprising residues 306–378 of tau protein, which adopt a combined cross-β/β-helix structure and define the seed for tau aggregation. Paired helical and straight filaments differ in their inter-protofilament packing, showing that they are ultrastructural polymorphs. These findings demonstrate that cryo-EM allows atomic characterization of amyloid filaments from patient-derived material, and pave the way for investigation of a range of neurodegenerative diseases.”

Cryo-EM structures of tau filaments from Alzheimer’s disease.
Fitzpatrick AWP, Falcon B, He S, Murzin AG, Murshudov G, Garringer HJ, Crowther RA, Ghetti B, Goedert M, Scheres SHW.
Nature. 2017 Jul 13;547(7662):185-190.
doi: 10.1038/nature23002. Epub 2017 Jul 5

mTOR

A recent study by Loic Verlingue and colleagues, published in the September 9 issue of Aging Cell. 2016 Sep 9 (doi: 10.1111/acel.12504), presents a comprehensive approach to examine the molecular determinants of lifespan using a Boolean model of geroconversion.

“The pharmaceutical inhibition of mTOR (comprising mTORC1 and/or mTORC2) is the most reproducible intervention to expand lifespan in preclinical models and correlates with a reduction of cell senescence proportions in many species including humans (Harrison et al., 2009; Anisimov et al., 2010; Popovich et al., 2014; Warner, 2015). Still, the pro-proliferative activity of mTORC1 is conceptually difficult to reconcile with its role in permanent growth arrest. Moreover, a prophylactic mTOR inhibition may inevitably expose individuals to well-known treatment’s toxicities (MacDonald & RAPAMUNE Global Study Group, 2001; Mahe et al., 2005; Ferte et al., 2011). Modeling the dose-related benefits and
risks of rapamycin treatment in the molecular network that controls senescence could therefore contribute to healthy lifespan expansion strategies for humans.”

“Geroconversion is a specific type of cell senescence resulting from the inappropriate activation of growth signals in nonproliferative cells.”

Anisimov VN, Zabezhinski MA, Popovich IG, Piskunova TS, Semenchenko AV, Tyndyk ML, Yurova MN, Antoch MP, Blagosklonny MV (2010) Rapamycin extends maximal lifespan in cancer-prone mice. Am. J. Pathol. 176, 2092–2097.

Ferte C, Paci A, Zizi M, Gonzales DB, Goubar A, Gomez-Roca C, Massard C, Sahmoud T, Andre F, Soria J-C (2011) Natural history, management and pharmacokinetics of everolimus-induced-oral ulcers: insights into compliance issues. Eur. J. Cancer 47, 2249–2255.

Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA (2009) Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395.

Popovich IG, Anisimov VN, Zabezhinski MA, Semenchenko AV, Tyndyk ML, Yurova MN, Blagosklonny MV (2014) Lifespan extension and cancer prevention in HER-2/neu transgenic mice treated with low intermittent doses of rapamycin. Cancer Biol. Ther. 15, 586–592.

MacDonald AS & RAPAMUNE Global Study Group (2001) A worldwide, phase III, randomized, controlled, safety and efficacy study of a sirolimus/cyclosporine regimen for prevention of acute rejection in recipients of primary mismatched renal allografts. Transplantation 71, 271–280.

Mahe E, Morelon E, Lechaton S, Sang K-HLQ, Mansouri R, Ducasse M-F, Mamzer-Bruneel M-F, de Prost Y, Kreis H, Bodemer C (2005) Cutaneous adverse events in renal transplant recipients receiving sirolimus-based therapy. Transplantation 79, 476–482.

Warner HR (2015) NIA’s intervention testing program at 10 years of age. Age (Dordr) 37, 22.

 

Zinc transporters and Alzheimer’s disease

Cognitive loss in zinc transporter-3 knock-out mice: a phenocopy for the synaptic and memory deficits of Alzheimer’s disease?

Adlard PA, et al. J Neurosci. 2010.

Authors

Adlard PA¹, Parncutt JM, Finkelstein DI, Bush AI.

Author information

• ¹Oxidation Biology Laboratory, The Mental Health Research Institute, Parkville, Victoria 3052, Australia.

Citation

J Neurosci. 2010 Feb 3;30(5):1631-6. doi: 10.1523/JNEUROSCI.5255-09.2010.

Abstract

Zinc transporter-3 (ZnT3) protein controls synaptic vesicular Zn(2+) levels, which is predicted to regulate normal cognitive function. Surprisingly, previous studies found that 6- to 10-week-old ZnT3 knock-out (KO) mice did not show impairment in the Morris water maze. We hypothesized that older ZnT3 KO animals would display a cognitive phenotype. Here, we report that ZnT3 KO mice exhibit age-dependent deficits in learning and memory that are manifest at 6 months but not at 3 months of age. These deficits are associated with significant alterations in key hippocampal proteins involved in learning and memory, as assessed by Western blot. These include decreased levels of the presynaptic protein SNAP25 (-46%; p < 0.01); the postsynaptic protein PSD95 (-37%; p < 0.01); the glutamate receptors AMPAR (-34%; p < 0.01), NMDAR2a (-64%; p < 0.001), and NMDAR2b (-49%; p < 0.05); the surrogate marker of neurogenesis doublecortin (-31%; p < 0.001); and elements of the BDNF pathway, pro-BDNF (-30%; p < 0.05) and TrkB (-22%; p < 0.01). In addition, there is a concomitant decrease in neuronal spine density (-6%; p < 0.05). We also found that cortical ZnT3 levels fall with age in wild-type mice (-50%; p < 0.01) in healthy older humans (ages, 48-91 years; r(2) = 0.47; p = 0.00019) and particularly in Alzheimer’s disease (AD) (-36%; p < 0.0001). Thus, age-dependent loss of transsynaptic Zn(2+) movement leads to cognitive loss, and since extracellular beta-amyloid is aggregated by and traps this pool of Zn(2+), the genetic ablation of ZnT3 may represent a phenocopy for the synaptic and memory deficits of AD.

PMID

 20130173 [PubMed – indexed for MEDLINE]

Sensory experiences of old people

A recent review found that … “Older people derive considerable pleasure and enjoyment from viewing nature, being and doing in nature which, in turn has a positive impact on their wellbeing and quality of life.”

BMC Geriatr. 2016 Jun 1;16(1):116. doi: 10.1186/s12877-016-0288-0.

How do older people describe their sensory experiences of the natural world? A systematic review of the qualitative evidence.

Orr N¹, Wagstaffe A², Briscoe S³, Garside R⁴.

• ¹European Centre for Environment and Human Health, University of Exeter Medical School, University of Exeter, Knowledge Spa, Truro, UK.
• ²The Sensory Trust, c/o Eden Project, Bodelva, Cornwall, UK.
• ³PenCLAHRC, University of Exeter Medical School, University of Exeter, Exeter, UK.
• ⁴European Centre for Environment and Human Health, University of Exeter Medical School, University of Exeter, Knowledge Spa, Truro, UK. r.garside@exeter.ac.uk.

 

… “There are over 46 million people living with dementia worldwide and this is estimated to increase to 131.5 million by 2050 [8]. The majority of people with dementia are living in the community [9], yet outdoor space has rarely been conceived of as a ‘dementia setting’ [10] (p.361), with the result that people living with dementia can sometimes feel ‘out of place in outdoor space’ [11] (p.283).”

… “We were particularly interested to explore if, and how, older people conceived of their contact with green/natural space in sensory terms and how this affected their experience.

… “When using natural settings, how do older people describe their sensory engagement with the outside world? Are there different experiences for different groups of people (e.g. those with dementia? Are there ways in which these experiences can be enhanced?”

 

8. Alzheimer’s Disease International. World Alzheimer Report 2015. London: Alzheimer’s Disease International (ADI); 2015.

9. Alzheimer’s Society. Dementia 2015: Aiming higher to transform lives. London: Alzheimer’s Society; 2015.

10. Blackman TIM, Mitchell L, Burton E, Jenks M, Parsons M, Raman S, et al. The accessibility of public spaces for people with dementia: A new priority for the ‘open city’. Disability & Soc. 2003;18(3):357–71. doi: 10.1080/0968759032000052914. [Cross Ref]

11. Brittain K, Corner L, Robinson L, Bond J. Ageing in place and technologies of place: the lived experience of people with dementia in changing social, physical and technological environments. Sociol Health Illn. 2010;32(2):272–87. doi: 10.1111/j.1467-9566.2009.01203.x. [PubMed] [Cross Ref]

 

Memory

How are permanent memories formed in the brain? It is generally agreed that memory involves strengthening the synapses that connect neurons in specific parts of the brain. This may be mediated by a lasting increase in the level of an isoform of an enzyme called PKMζ (pronounced PKM zeta) that can be rendered inherently active. However, mice in which the gene for PKMζ had been knocked out have been found to capable of forming long-term memories. Panayiotis Tsokas and colleagues carried out a study to suggest that a different enzyme, PKCι/λ (pronounced PKM iota lambda) is upregulated in the absence of PKMζ and may take over some functions of PKMζ.

Elife. 2016 May 17;5. pii: e14846. doi: 10.7554/eLife.14846.

Compensation of PKMζ in long-term potentiation and spatial long-term memory in mutant mice.

Tsokas P^1,2, Hsieh C¹, Yao Y¹, Lesburguères E³, Wallace EJ¹, Tcherepanov A¹, Jothianandan D¹, Hartley BR¹, Pan L¹, Rivard B¹, Farese RV⁴, Sajan MP⁴, Bergold PJ¹, Hernández AI⁵, Cottrell JE², Shouval HZ⁶, Fenton AA^1,3, Sacktor TC^1,2,7.

 

• ¹Department of Physiology and Pharmacology, The Robert F Furchgott Center for Neural and Behavioral Science, State University of New York Downstate Medical Center, Brooklyn, United States.
• ²Department of Anesthesiology, State University of New York Downstate Medical Center, Brooklyn, United States.
• ³Center for Neural Science, New York University, New York, United States.
• ⁴Department of Internal Medicine, James A Haley Veterans Hospital, University of South Florida, Tampa, United States.
• ⁵Department of Pathology, State University of New York Downstate Medical Center, Brooklyn, United States.
• ⁶Department of Neurobiology and Anatomy, University of Texas Medical School at Houston, Houston, United States.
• ⁷Department of Neurology, State University of New York Downstate Medical Center, Brooklyn, United States.

 

Screening for anti-aging molecules

There is a recent review paper about screening for anti-aging molecules …

Finding Ponce de Leon’s Pill: Challenges in Screening for Anti-Aging Molecules

Surinder Kumar and David Lombard

Aging is characterized by the progressive accumulation of degenerative changes, culminating in impaired function and increased probability of death. It is the major risk factor for many human pathologies – including cancer, type 2 diabetes, and cardiovascular and neurodegenerative diseases – and consequently exerts an enormous social and economic toll. The major goal of aging research is to develop interventions that can delay the onset of multiple age-related diseases and prolong healthy lifespan (healthspan). The observation that enhanced longevity and health can be achieved in model organisms by dietary restriction or simple genetic manipulations has prompted the hunt for chemical compounds that can increase lifespan. Most of the pathways that modulate the rate of aging in mammals have homologs in yeast, flies, and worms, suggesting that initial screening to identify such pharmacological interventions may be possible using invertebrate models. In recent years, several compounds have been identified that can extend lifespan in invertebrates, and even in rodents. Here, we summarize the strategies employed, and the progress made, in identifying compounds capable of extending lifespan in organisms ranging from invertebrates to mice and discuss the formidable challenges in translating this work to human therapies.

 

Early-onset Alzheimer disease revisited

There is a recent review revisiting the molecular genetics of early-onset Alzheimer disease.

Abstract:

As the discovery of the Alzheimer disease (AD) genes, APP, PSEN1, and PSEN2, in families with autosomal dominant early-onset AD (EOAD), gene discovery in familial EOAD came more or less to a standstill. Only 5% of EOAD patients are carrying a pathogenic mutation in one of the AD genes or a APOE risk allele ε4, most of EOAD patients remain unexplained. Here, we aimed at summarizing the current knowledge of EOAD genetics and its role in ongoing approaches to understand the biology of AD and disease symptomatology as well as developing new therapeutics. Next, we explored the possible molecular mechanisms that might underlie the missing genetic etiology of EOAD and discussed how the use of massive parallel sequencing technologies triggered novel gene discoveries. To conclude, we commented on the relevance of reinvestigating EOAD patients as a means to explore potential new avenues for translational research and therapeutic discoveries.

Alzheimers Dement. 2016 Mar 23. pii: S1552-5260(16)00079-0.

DOI: http://dx.doi.org/10.1016/j.jalz.2016.01.012

Molecular genetics of early-onset Alzheimer disease revisited.

Cacace R¹, Sleegers K¹, Van Broeckhoven C².

• ¹Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
• ²Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. Electronic address: christine.vanbroeckhoven@molgen.vib-ua.be.

Protective effects of sirtuins

A recent review highlights the protective effects of sirtuins in cardiovascular disease …

“Sirtuins (Sirt1–Sirt7) comprise a family of nicotinamide adenine dinucleotide (NAD⁺)-dependent enzymes. While deacetylation reflects their main task, some of them have deacylase, adenosine diphosphate-ribosylase, demalonylase, glutarylase, and desuccinylase properties. Activated upon caloric restriction and exercise, they control critical cellular processes in the nucleus, cytoplasm, and mitochondria to maintain metabolic homeostasis, reduce cellular damage and dampen inflammation—all of which serve to protect against a variety of age-related diseases, including cardiovascular pathologies. This review focuses on the cardiovascular effects of Sirt1, Sirt3, Sirt6, and Sirt7.”

Sirt1 protects from endothelial dysfunction, atherothrombosis, diet-induced obesity, type 2 diabetes, liver steatosis, and myocardial infarction.

Sirt3 provides beneficial effects in the context of left ventricular hypertrophy, cardiomyopathy, oxidative stress, metabolic homeostasis, and dyslipidaemia.

Sirt6 is implicated in ameliorating dyslipidaemia, cellular senescence, and left ventricular hypertrophy.

Sirt7 plays a role in lipid metabolism and cardiomyopathies.

Eur Heart J. 2015 Dec 21;36(48):3404-12. doi: 10.1093/eurheartj/ehv290. Epub 2015 Jun 25.
Protective effects of sirtuins in cardiovascular diseases: from bench to bedside.
Winnik S, Auwerx J, Sinclair DA, Matter CM.

Sightlines

The Sightlines Project investigates how well Americans are doing in each of the three areas that are critical to well-being as people age: financial security, social engagement and healthy living. Do the trends over the last 15 years bode well or do they raise concerns regarding our capacity to thrive as individuals and as a nation?

The findings are based on analyses of eight nationally representative, high quality, multi-year studies over two decades involving more than 1.2 million Americans. The learnings are intended to stir national debate, guide policy development, stimulate entrepreneurial innovation, and encourage personal choices that enhance independent, 100-year lives.

KEY FINDINGS 
Healthy Living, defined as avoiding risky behaviors (smoking, excessive drinking, drug use, etc.) and making healthy choices day to day (eating well, exercising, etc.), is known to be beneficial. Americans have made substantial progress in several areas, while others challenges remain or have actually increased.

Most surprising:

• Smoking –the top preventable cause of morbidity and early mortality – is declining in every age group.
• For the first time in decades, more Americans are exercising regularly. More than half of Millennials (ages 25-34) are getting the recommended amount of exercise.
• Sitting, which has emerged as an independent risk factor for health, is steeply increasing.
• Problems with diet and sleep are widespread and show no signs of abating.

Financial security across the life span is a growing challenge for longer lives. Financial security has deteriorated from 2000 to 2014, particularly among the least educated, who are more likely to live at or near poverty, lack emergency resources, and are less likely to invest in their financial futures.

Most surprising:

• A 15-year decline in health insurance coverage among the most vulnerable (those without high school education) has reversed since the implementation of the Affordable Care Act, decreasing the likelihood that the financial security of those in this group will be decimated by a health event.
• Millennials (adults ages 25 to 34) are facing uphill struggles. The incomes of the less educated are often at or near poverty levels while those who went to college are 50% more likely to carry debt and the average debt in this group is 5 times higher than their predecessors carried just 15 years ago.
• Fewer Americans (two out of three) establish retirement savings plans before age 55. Among those who are ineligible for employer-based plans, only one in three is participating in a plan.

Social engagement, central to long and healthy lives, includes both meaningful relationships and participation in communities. Social engagement is declining along many traditional indicators. It is too soon to tell whether new forms of technology-mediated social engagement – SMS, chat, facetime, posting and tweeting – are providing social benefits and how they complement face to face engagement.

Most surprising:

• With the exception of 35-44 year olds, community engagement has declined. Interactions with neighbors – who represent physically-accessible and often helpful relationships – are becoming less common.
• Compared to their counterparts only 20 years ago, members of the Baby Boom generation, are less likely to be married, have weaker ties to family, friends, and neighbors, and are less likely to engage in religious or community activities.
• Longer lives mean that marriages survive as well. Fifty-three percent of Americans over 75 are married, up from 42 percent in 2003.

http://sightlinesproject.stanford.edu./overview.html