Pain processing in older adults with dementia-related cognitive impairment is associated with frontal neurodegeneration.

Experimental pain research has shown that pain processing seems to be heightened in dementia. It is unclear which neuropathological changes underlie these alterations. This study examined whether differences in pressure pain sensitivity and endogenous pain inhibition (conditioned pain modulation (CPM)) between individuals with a dementia-related cognitive impairment (N=23) and healthy controls (N=35) are linked to dementia-related neurodegeneration. Pain was assessed via self-report ratings and by analyzing the facial expression of pain using the Facial Action Coding System. We found that cognitively impaired individuals show decreased CPM inhibition as assessed by facial responses compared to healthy controls, which was mediated by decreased gray matter volume in the medial orbitofrontal and anterior cingulate cortex in the patient group. This study confirms previous findings of intensified pain processing in dementia when pain is assessed using non-verbal responses. Our findings suggest that a loss of pain inhibitory functioning caused by structural changes in prefrontal areas might be one of the underlying mechanisms responsible for amplified pain responses in individuals with a dementia-related cognitive impairment.

Basal forebrain cholinergic system in the dementias: Vulnerability, resilience, and resistance.

The basal forebrain cholinergic neurons (BFCN) provide the primary source of cholinergic innervation of the human cerebral cortex. They are involved in the cognitive processes of learning, memory, and attention. These neurons are differentially vulnerable in various neuropathologic entities that cause dementia. This review summarizes the relevance to BFCN of neuropathologic markers associated with dementias, including the plaques and tangles of Alzheimer's disease (AD), the Lewy bodies of diffuse Lewy body disease, the tauopathy of frontotemporal lobar degeneration (FTLD-TAU) and the TDP-43 proteinopathy of FTLD-TDP. Each of these proteinopathies has a different relationship to BFCN and their corticofugal axons. Available evidence points to early and substantial degeneration of the BFCN in AD and diffuse Lewy body disease. In AD, the major neurodegenerative correlate is accumulation of phosphotau in neurofibrillary tangles. However, these neurons are less vulnerable to the tauopathy of FTLD. An intriguing finding is that the intracellular tau of AD causes destruction of the BFCN, whereas that of FTLD does not. This observation has profound implications for exploring the impact of different species of tauopathy on neuronal survival. The proteinopathy of FTLD-TDP shows virtually no abnormal inclusions within the BFCN. Thus, the BFCN are highly vulnerable to the neurodegenerative effects of tauopathy in AD, resilient to the neurodegenerative effect of tauopathy in FTLD and apparently resistant to the emergence of proteinopathy in FTLD-TDP and perhaps also in Pick's disease. Investigations are beginning to shed light on the potential mechanisms of this differential vulnerability and their implications for therapeutic intervention.

Focal white matter lesions induce long-lasting axonal degeneration, neuroinflammation and behavioral deficits.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) with episodes of inflammatory demyelination and remyelination. While remyelination has been linked with functional recovery in MS patients, there is evidence of ongoing tissue damage despite complete myelin repair. In this study, we investigated the long-term consequences of an acute demyelinating white matter CNS lesion. For this purpose, acute demyelination was induced by 5-week-cuprizone intoxication in male C57BL/6 J mice, and the tissues were examined after a 7-month recovery period. While myelination and oligodendrocyte densities appeared normal, ongoing axonal degeneration and glia cell activation were found in the remyelinated corpus callosum. Neuropathologies were paralleled by subtle gait abnormalities evaluated using DigiGait™ high speed ventral plane videography. Gene array analyses revealed increased expression levels of various inflammation related genes, among protein kinase c delta (PRKCD). Immunofluorescence stains revealed predominant microglia/macrophages PRKCD expression in both, cuprizone tissues and post-mortem MS lesions. These results support the hypothesis that chronic microglia/macrophages driven tissue injury represents a key aspect of progressive neurodegeneration and functional decline in MS.

"Let Food Be Thy Medicine": Gluten and Potential Role in Neurodegeneration.

Wheat is a most favored staple food worldwide and its major protein is gluten. It is involved in several gluten dependent diseases and lately was suggested to play a role in non-celiac autoimmune diseases. Its involvement in neurodegenerative conditions was recently suggested but no cause-and-effect relationship were established. The present narrative review expands on various aspects of the gluten-gut-brain axes events, mechanisms and pathways that connect wheat and gluten consumption to neurodegenerative disease. Gluten induced dysbiosis, increased intestinal permeabillity, enteric and systemic side effects, cross-reactive antibodies, and the sequence of homologies between brain antigens and gluten are highlighted. This combination may suggest molecular mimicry, alluding to some autoimmune aspects between gluten and neurodegenerative disease. The proverb of Hippocrates coined in 400 BC, "let food be thy medicine," is critically discussed in the frame of gluten and potential neurodegeneration evolvement.

Neurodegeneration, Alzheimer's disease biomarkers, and longitudinal verbal learning and memory performance in late middle age.

This study examined the effect of neurodegeneration, and its interaction with Alzheimer's disease (AD) cerebrospinal fluid biomarkers, on longitudinal verbal learning and memory performance in cognitively unimpaired (CU) late middle-aged adults. Three hundred and forty-two CU adults (cognitive baseline mean age = 58.4), with cerebrospinal fluid and structural MRI, completed 2-10 (median = 5) cognitive assessments. Learning and memory were assessed using the Rey Auditory Verbal Learning Test (RAVLT). We used sequential comparison of nested linear mixed effects models to analyze the data. Model selection preserved a significant ptau181/Aß42 × global atrophy × age interaction; individuals with less global atrophy and lower ptau181/Aß42 levels had less learning and delayed recall decline than individuals with more global atrophy and/or higher levels of ptau181/Aß42. The hippocampal volume × age × ptau181/Aß42 interaction was not significant. Findings suggest that in a sample of CU late middle-aged adults, individuals with AD biomarkers, global atrophy, or both evidence greater verbal learning and memory decline than individuals without either risk factor.

Degeneration of core neural tracts for emotional regulation in a patient with traumatic brain injury: A case report.

RATIONALE: Several brain structures, including the orbital prefrontal cortex, ventrolateral prefrontal cortex, dorsolateral prefrontal cortex, amygdala, and anterior cingulate cortex, are considered key structures in the neural circuitry underlying emotion regulation. We report on a patient showing behavior changes and degeneration of core neural tracts for emotional regulation following traumatic brain injury (TBI). PATIENT CONCERNS: A 51-year-old male patient suffered an in-car accident. The patient lost consciousness for approximately 30 days, and his Glasgow Coma Scale score was 3. He underwent stereotactic drainage for traumatic intraventricular and intracerebral hemorrhages. At approximately 6.5-year after onset, he began to show disinhibition behaviors such as shouting with anger, which worsened over time. At approximately 8-year after onset, he showed severe depression signs and disinhibition, including violence. DIAGNOSES: The patient who showed delayed-onset behavioral changes (disinhibition and depression). INTERVENTIONS: Diffusion tensor imaging data were acquired at 3 months and 8 years after TBI onset. OUTCOMES: The patient showed degeneration of core neural tracts for emotional regulation that was associated with delayed behavioral changes following TBI. On both 3-month and 8-year diffusion tensor tractographies (DTTs), the right dorsolateral prefronto-thalamic tract, ventrolateral prefronto-thalamic tract, orbital prefronto-thalamic tract, uncinate fasciculus, and both cinguli were reconstructed whereas other neural tracts were not reconstructed. Compared with the 3-month DTT, all reconstructed neural tracts on the 8-year DTT were narrow, except for the left cingulum, which showed new transcallosal fibers between both anterior cingula. The fractional anisotropy and tract volume of all reconstructed neural tracts were lower on the 8-year DTT than the 3-month DTT, except for the tract volume of left cingulum. LESSONS: The evaluation of dorsolateral, ventrolateral, and orbital prefronto-thalamic tract, uncinate fasciculus, and cingulum using follow-up DTTs is useful when a patient with TBI shows delayed-onset behavioral problems.

Brain Neurodegeneration in the Chronic Stage of the Survivors from Severe Non-Missile Traumatic Brain Injury: A Voxel-Based Morphometry Within-Group at One versus Nine Years from a Head Injury.

The long-term time course of neuropathological changes occurring in survivors from severe traumatic brain injury (TBI) remains uncertain. We investigated the brain morphometry and memory performance modifications within the same group of severe non-missile traumatic brain injury patients (nmTBI) after about ∼one year and at ∼ nine years from injury. Brain magnetic resonance imaging (MRI) measurements were performed with voxel-based morphometry (VBM) to determine specific changes in the gray matter (GM) and white matter (WM) and the overall gray matter volume modifications (GMV) and white matter volume modifications (WMV). Contemporarily, memory-tests were also administered. In comparison with healthy control subjects (HC), those with nmTBI showed a significant change and volume reduction in the GM and WM and also in the GMV and WMV after ∼one year; conversely, ∼nine years after injury, neurodegenerative changes spared the GM and GMV, but a prominent loss was detected in WMV and in WM sites, such as the superior longitudinal fasciculi, the body of the corpus callosum, the optic radiation, and the uncinate fasciculus. Memory performance at ∼one year in comparison with ∼nine years was stable with a subtle but significant trend toward recovery. These data demonstrate that patients with nmTBI undergo neurodegenerative processes during the chronic stage affecting mainly the cerebral WM rather than GM. Despite these anatomical brain parenchyma losses, memory performance tends to be stable or even slightly recovered. These results suggest possible correlations between progressive demyelinization and/or neuropsychiatric changes other than memory performance, and support possible treatments to prevent long-term WM degeneration of the examined nmTBI.

Fundamental Clock of Biological Aging: Convergence of Molecular, Neurodegenerative, Cognitive and Psychiatric Pathways: Non-Equilibrium Thermodynamics Meet Psychology.

In humans, age-associated degrading changes, widely observed in molecular and cellular processes underly the time-dependent decline in spatial navigation, time perception, cognitive and psychological abilities, and memory. Cross-talk of biological, cognitive, and psychological clocks provides an integrative contribution to healthy and advanced aging. At the molecular level, genome, proteome, and lipidome instability are widely recognized as the primary causal factors in aging. We narrow attention to the roles of protein aging linked to prevalent amino acids chirality, enzymatic and spontaneous (non-enzymatic) post-translational modifications (PTMs SP), and non-equilibrium phase transitions. The homochirality of protein synthesis, resulting in the steady-state non-equilibrium condition of protein structure, makes them prone to multiple types of enzymatic and spontaneous PTMs, including racemization and isomerization. Spontaneous racemization leads to the loss of the balanced prevalent chirality. Advanced biological aging related to irreversible PTMs SP has been associated with the nontrivial interplay between somatic (molecular aging) and mental (psychological aging) health conditions. Through stress response systems (SRS), the environmental and psychological stressors contribute to the age-associated "collapse" of protein homochirality. The role of prevalent protein chirality and entropy of protein folding in biological aging is mainly overlooked. In a more generalized context, the time-dependent shift from enzymatic to the non-enzymatic transformation of biochirality might represent an important and yet underappreciated hallmark of aging. We provide the experimental arguments in support of the racemization theory of aging.

Deletion of exons encoding carboxypeptidase domain of Nna1 results in Purkinje cell degeneration (pcd) phenotype.

Purkinje cell degeneration (pcd) was first identified in a spontaneous mouse mutant showing cerebellar ataxia. In addition to cerebellar Purkinje cells (PCs), retinal photoreceptors, mitral cells in the olfactory bulb, and a discrete subpopulation of thalamic neurons also degenerate in the mutant brains. The gene responsible for the pcd mutant is Nna1, also known as ATP/GTP binding protein 1 or cytosolic carboxypeptidase-like 1, which encodes a zinc carboxypeptidase protein. To investigate pathogenesis of the pcd mutation in detail, we generated a conditional Nna1 allele targeting the carboxypeptidase domain at C-terminus. After Cre recombination and heterozygous crossing, we generated Nna1 knockout (KO) mice and found that the Nna1 KO mice began to show cerebellar ataxia at postnatal day 20 (P20). Most PCs degenerated until 4-week-old, except lobule X. Activated microglia and astrocytes were also observed in the Nna1 KO cerebellum. In the mutant brain, the Nna1 mRNA level was dramatically reduced, suggesting that nonsense-mediated mRNA decay occurs in it. Since the Nna1 protein acts as a de-glutamatase on the C-terminus of α-tubulin and ß-tubulin, increased polyglutamylated tubulin was detected in the Nna1 KO cerebellum. In addition, the endoplasmic reticulum stress marker, C/EBP homologous protein (CHOP), was up-regulated in the mutant PCs. We report the generation of a functional Nna1 conditional allele and possible mechanisms of PC death in the Nna1 KO in the cerebellum. OPEN PRACTICES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

Cognitive reserve maps the core loci of neurodegeneration in corticobasal degeneration.

BACKGROUND AND PURPOSE: Cognitively stimulating life experiences and activities are deemed to moderate the clinical impact of brain damage progressively building a neural and cognitive reserve (CR). CR has been studied extensively in various neurodegenerative disorders, but not in corticobasal degeneration (CBD). METHODS: Using Statistical Parametric Mapping 8, years of education, as a determinant of CR, was correlated with tracer uptake on positron emission tomography with 18 F-fluorodeoxyglucose, as a marker of neurodegeneration, in 35 patients with various phenotypes of CBD, including a cognitive-motor composite score or symptoms duration as covariates for controlling disease stage. RESULTS: A cluster of relative hypometabolism was found associated with higher education in the left inferior regions of pre- and post-rolandic gyri and insula, which represent typical loci of neurodegeneration in CBD regardless of clinical presentation. CONCLUSIONS: The present findings extend to CBD the evidence gathered in other neurodegenerative disorders that a higher CR has a protective effect against the clinical manifestations of brain degeneration.

Curcumin Ameliorates Neuroinflammation, Neurodegeneration, and Memory Deficits in p25 Transgenic Mouse Model that Bears Hallmarks of Alzheimer's Disease.

Several studies have indicated that neuroinflammation is indeed associated with neurodegenerative disease pathology. However, failures of recent clinical trials of anti-inflammatory agents in neurodegenerative disorders have emphasized the need to better understand the complexity of the neuroinflammatory process in order to unravel its link with neurodegeneration. Deregulation of Cyclin-dependent kinase 5 (Cdk5) activity by production of its hyperactivator p25 is involved in the formation of tau and amyloid pathology reminiscent of Alzheimer's disease (AD). Recent studies show an association between p25/Cdk5 hyperactivation and robust neuroinflammation. In addition, we recently reported the novel link between the p25/Cdk5 hyperactivation-induced inflammatory responses and neurodegenerative changes using a transgenic mouse that overexpresses p25 (p25Tg). In this study, we aimed to understand the effects of early intervention with a potent natural anti-inflammatory agent, curcumin, on p25-mediated neuroinflammation and the progression of neurodegeneration in p25Tg mice. The results from this study showed that curcumin effectively counteracted the p25-mediated glial activation and pro-inflammatory chemokines/cytokines production in p25Tg mice. Moreover, this curcumin-mediated suppression of neuroinflammation reduced the progression of p25-induced tau/amyloid pathology and in turn ameliorated the p25-induced cognitive impairments. It is widely acknowledged that to treat AD, one must target the early-stage of pathological changes to protect neurons from irreversible damage. In line with this, our results demonstrated that early intervention of inflammation could reduce the progression of AD-like pathological outcomes. Moreover, our data provide a rationale for the potential use of curcuminoids in the treatment of inflammation associated neurodegenerative diseases.

Cognitive performance correlates with the degree of dopaminergic degeneration in the associative part of the striatum in non-demented Parkinson's patients.

Parkinson's disease (PD) patients show cognitive deficits that are relevant in terms of prognosis and quality of life. Degeneration of striatal dopaminergic afferents proceeds from dorsal/caudal to anterior/ventral and is discussed to account for some of these symptoms. Treatment with dopamine (DA) has differential effects on cognitive dysfunctions, improving some and worsening others. We hypothesized that cognitive performance during the dopaminergic OFF state correlates with DAT availability in the associative striatum. 16 PD patients underwent motor and cognitive examination ON and OFF DA. Global cognition was measured using the Montréal Cognitive Assessment (MoCA) test and executive functioning using a Stroop test. Nigrostriatal dopaminergic innervation was characterized with [123I]FP-CIT SPECT. A connectivity atlas of the striatum was used to assess DAT availability in functionally defined striatal subregions. Correlations between imaging data and behavioral data OFF medication were calculated. Correlations between DAT availability and MoCA performance in the dopaminergic OFF state was strongest in the associative part of the striatum (r = 0.674, p = 0.004). MoCA test performance did not differ between the ON and the OFF state. There was no correlation of DAT availability with Stroop performance in the OFF state but performance was significantly better during the ON state. Not only motor but also cognitive dysfunctions in PD are associated with striatal dopaminergic depletion. Cognitive decline in non-demented PD patients goes along with nigrostriatal degeneration, most pronounced in the associative subdivision of the striatum. In addition, the present findings suggest that executive dysfunctions are ameliorated by DA whereas global cognition is not improved by dopaminergic medication.

Neurons vs. Germline: A War of Hormetic Tradeoffs.

The process of human ageing is significantly dependent upon events which are currently shaping humanity. One such event is the seemingly inexorable progress of technology, and specifically, digital communications technology. Technology and biology are tightly interconnected, and this has a direct relevance on how our own ageing mechanisms are evolving and adapting to the change. One way technology may affect biological ageing is based on the concept of information exposure which acts as a hormetic stimulus and up-regulates neuronal stress response pathways. In this way, neurons become increasingly more likely to acquire repair resources and function for longer, with a consequent overall improvement in healthy lifespan. At the same time, germline repair mechanisms may need to be downgraded in order to accommodate a tradeoff: a corresponding escalation of repairs in neurons. In this Opinion paper, it is discussed that how a meaningful and intentional integration with technology, which hormetically challenges our cognition, may redress the conflict for resources between the soma and the germline, and result in a reduction of age-related dysfunction in the subjects.

Synthesis and neuroprotective effects of the complex nanoparticles of iron and sapogenin isolated from the defatted seeds of Camellia oleifera.

CONTEXT: The defatted seeds of Camellia oleifera var. monosperma Hung T. Chang (Theaceae) are currently discarded without effective utilization. However, sapogenin has been isolated and shows antioxidative, anti-inflammatory and analgesic activities suggestive of its neuroprotective function. OBJECTIVE: In order to improve the activities of sapogenin, the nanoparticles of iron-sapogenin have been synthesized, and the neuroprotective effects are evaluated. MATERIALS AND METHODS: Structural characters of the nanoparticles were analyzed, and the antioxidant effect was assessed by DPPH method, and the neuroprotective effect was evaluated by rotenone-induced neurodegeneration in Kunming mice injected subcutaneously into the back of neck with rotenone (50 mg/kg/day) for 6 weeks and then treated by tail intravenous injection with the iron-sapogenin at the dose of 25, 50 and 100 mg/kg for 7 days. Mice behaviour and neurotransmitters were tested. RESULTS: The product had an average size of 162 nm with spherical shape, and scavenged more than 90% DPPH radicals at 0.8 mg/mL concentration. It decreased behavioural disorder and malondialdehyde content in mice brain, and increased superoxide dismutase activity, tyrosine hydroxylase expression, dopamine and acetylcholine levels in brain in dose dependence, and their maximum changes were respectively up to 60.83%, 25.17%, 22.13%, 105.26%, 42.17% and 22.89% as compared to vehicle group. Iron-sapogenin nanoparticle shows significantly better effects than the sapogenin. DISCUSSION AND CONCLUSION: Iron-sapogenin alleviates neurodegeneration of mice injured by neurotoxicity of rotenone, it is a superior candidate of drugs for neuroprotection.

Systemic TNF-α produces acute cognitive dysfunction and exaggerated sickness behavior when superimposed upon progressive neurodegeneration.

Inflammation influences chronic neurodegeneration but its precise roles are not yet clear. Systemic inflammation caused by infection, trauma or co-morbidity can alter the brain's inflammatory status, produce acute cognitive impairments, such as delirium, and drive new pathology and accelerated decline. Consistent with this, elevated systemic TNF-α is associated with more rapid cognitive decline over 6months in Alzheimer's disease patients. In the current study we challenged normal animals and those with existing progressive neurodegeneration (ME7 prion disease) with TNF-α (i.p.) to test the hypothesis that this cytokine has differential effects on cognitive function, sickness behavior and features of underlying pathology contingent on the animals' baseline condition. TNF-α (50µg/kg) had no impact on performance of normal animals (normal brain homogenate; NBH) on working memory (T-maze) but produced acute impairments in ME7 animals similarly challenged. Plasma TNF-α and CCL2 levels were equivalent in NBH and ME7 TNF-challenged animals but hippocampal and hypothalamic transcription of IL-1ß, TNF-α and CCL2 and translation of IL-1ß were higher in ME7+TNF-α than NBH+TNF-α animals. TNF-α produced an exaggerated sickness behavior response (hypothermia, weight loss, inactivity) in ME7 animals compared to that in NBH animals. However a single challenge with this dose was not sufficient to produce de novo neuronal death, synaptic loss or tau hyperphosphorylation that was distinguishable from that arising from ME7 alone. The data indicate that acutely elevated TNF-α has robust acute effects on brain function, selectively in the degenerating brain, but more sustained levels may be required to significantly impact on underlying neurodegeneration.

Tool use disorders in neurodegenerative diseases: Roles of semantic memory and technical reasoning.

In the field of apraxia, it has been suggested that the ability to use tools and objects in daily life depends not only on semantic knowledge about tool function and context of use but also on technical reasoning about mechanical properties of tools and objects. The aim of the present work was to assess tool use abilities regarding these hypotheses in patients with neurodegenerative diseases and reduced autonomy. Performance of patients with Alzheimer's disease (AD) (n = 31), semantic dementia (SD) (n = 16) and corticobasal syndrome (CBS) (n = 7) was compared to that of healthy control participants (n = 31) in familiar tool use tasks, functional/contextual associations and mechanical problem solving (MPS). A conversion method was applied to data in order to avoid ceiling effects. Tool use disorders were found in all patient groups but the underlying reasons were different. Patients with SD had difficulties in imagining and selecting familiar tools due to the semantic loss but they performed in normal range in MPS tasks. Interestingly, they performed better with only one tool and its corresponding object, which is interpreted as a partial compensation of semantic loss by spared technical reasoning. Patients with CBS exhibited the reverse pattern, that is, MPS deficits without semantic loss. However, additional qualitative research is needed to disentangle the relative contributions of motor and technical reasoning deficits to this pattern. Both of these profiles were found in patients with AD. For all that, these patients did not commit the same errors as stroke patients with left brain-damage documented in previous works. Several hypotheses are proposed to account for the specificity of tool use disorders in neurodegenerative diseases, and recommendations are provided to caregivers.

Postischemic Anhedonia Associated with Neurodegenerative Changes in the Hippocampal Dentate Gyrus of Rats.

Poststroke depression is one of the major symptoms observed in the chronic stage of brain stroke such as cerebral ischemia. Its pathophysiological mechanisms, however, are not well understood. Using the transient right middle cerebral artery occlusion- (MCAO-, 90 min) operated rats as an ischemia model in this study, we first observed that aggravation of anhedonia spontaneously occurred especially after 20 weeks of MCAO, and it was prevented by chronic antidepressants treatment (imipramine or fluvoxamine). The anhedonia specifically associated with loss of the granular neurons in the ipsilateral side of hippocampal dentate gyrus and was also prevented by an antidepressant imipramine. Immunohistochemical analysis showed increased apoptosis inside the granular cell layer prior to and associated with the neuronal loss, and imipramine seemed to recover the survival signal rather than suppressing the death signal to prevent neurons from apoptosis. Proliferation and development of the neural stem cells were increased transiently in the subgranular zone of both ipsi- and contralateral hippocampus within one week after MCAO and then decreased and almost ceased after 6 weeks of MCAO, while chronic imipramine treatment prevented them partially. Overall, our study suggests new insights for the mechanistic correlation between poststroke depression and the delayed neurodegenerative changes in the hippocampal dentate gyrus with effective use of antidepressants on them.

The Spontaneous Ataxic Mouse Mutant Tippy is Characterized by a Novel Purkinje Cell Morphogenesis and Degeneration Phenotype.

This study represents the first detailed analysis of the spontaneous neurological mouse mutant, tippy, uncovering its unique cerebellar phenotype. Homozygous tippy mutant mice are small, ataxic, and die around weaning. Although the cerebellum shows grossly normal foliation, tippy mutants display a complex cerebellar Purkinje cell phenotype consisting of abnormal dendritic branching with immature spine features and patchy, non-apoptotic cell death that is associated with widespread dystrophy and degeneration of the Purkinje cell axons throughout the white matter, the cerebellar nuclei, and the vestibular nuclei. Moderate anatomical abnormalities of climbing fiber innervation of tippy mutant Purkinje cells were not associated with changes in climbing fiber-EPSC amplitudes. However, decreased ESPC amplitudes were observed in response to parallel fiber stimulation and correlated well with anatomical evidence for patchy dark cell degeneration of Purkinje cell dendrites in the molecular layer. The data suggest that the Purkinje neurons are a primary target of the tippy mutation. Furthermore, we hypothesize that the Purkinje cell axonal pathology together with disruptions in the balance of climbing fiber and parallel fiber-Purkinje cell input in the cerebellar cortex underlie the ataxic phenotype in these mice. The constellation of Purkinje cell dendritic malformation and degeneration phenotypes in tippy mutants is unique and has not been reported in any other neurologic mutant. Fine mapping of the tippy mutation to a 2.1 MB region of distal chromosome 9, which does not encompass any gene previously implicated in cerebellar development or neuronal degeneration, confirms that the tippy mutation identifies novel biology and gene function.

Aging-related neurodegeneration eliminates male courtship choice in Drosophila.

Choices between 2 options, one liked and one disliked, are effortless for an animal, whereas those among 2 equally liked options are more difficult to determine and might depend on an unknown mechanism. Here, we report that in the fruit fly Drosophila melanogaster, both younger virgin females and older ones are "liked options" to males. However, when given the choice, males tend to be fastidious and prefer younger virgin females to older ones. Besides, aging eliminates males' preference for younger mates, which can be mimicked by ectopically expressing the human amyloid precursor protein in their central nervous system. Furthermore, we examined the effect of neurodegeneration in Drosophila courtship circuit and confirmed that male courtship preference for younger mates was abrogated by neurodegeneration. Our work, thus characterizes a novel choice behavior that can be decisions after comparison and also reveals the critical role of neurodegeneration in this behavior, which provides new insights on decision-making mechanisms.

Beyond and below the cortex: the contribution of striatal dysfunction to cognition and behaviour in neurodegeneration.

Investigations of cognitive and behavioural changes in neurodegeneration have been mostly focussed on how cortical changes can explain these symptoms. In the proposed review, we will argue that the striatum has been overlooked as a critical nexus in understanding the generation of such symptoms. Although the striatum is historically more associated with motor dysfunction, there is increasing evidence from functional neuroimaging studies in the healthy that striatal regions modulate behaviour and cognition. This should not be surprising, as the striatum has strong anatomical connections to many cortical regions including the frontal, temporal and insula lobes, as well as some subcortical regions (amygdala, hippocampus). To date, however, it is largely unclear to what extent striatal regions are affected in many neurodegenerative conditions-and if so, how striatal dysfunction can potentially influence cognition and behaviour. The proposed review will examine the existing evidence of striatal changes across selected neurodegenerative conditions (Parkinson's disease, progressive supranuclear palsy, Huntington's disease, motor neuron disease, frontotemporal dementia and Alzheimer's disease), and will document their link with the cognitive and behavioural impairments observed. Thus, by reviewing the varying degrees of cortical and striatal changes in these conditions, we can start outlining the contributions of the striatal nexus to cognitive and behavioural symptoms. In turn, this knowledge will inform future studies investigating corticostriatal networks and also diagnostic strategies, disease management and future therapeutics of neurodegenerative conditions.