Anterior thalamic nuclei neurons sustain memory.

A hippocampal-diencephalic-cortical network supports memory function. The anterior thalamic nuclei (ATN) form a key anatomical hub within this system. Consistent with this, injury to the mammillary body-ATN axis is associated with examples of clinical amnesia. However, there is only limited and indirect support that the output of ATN neurons actively enhances memory. Here, in rats, we first showed that mammillothalamic tract (MTT) lesions caused a persistent impairment in spatial working memory. MTT lesions also reduced rhythmic electrical activity across the memory system. Next, we introduced 8.5 Hz optogenetic theta-burst stimulation of the ATN glutamatergic neurons. The exogenously-triggered, regular pattern of stimulation produced an acute and substantial improvement of spatial working memory in rats with MTT lesions and enhanced rhythmic electrical activity. Neither behaviour nor rhythmic activity was affected by endogenous stimulation derived from the dorsal hippocampus. Analysis of immediate early gene activity, after the rats foraged for food in an open field, showed that exogenously-triggered ATN stimulation also increased Zif268 expression across memory-related structures. These findings provide clear evidence that increased ATN neuronal activity supports memory. They suggest that ATN-focused gene therapy may be feasible to counter clinical amnesia associated with dysfunction in the mammillary body-ATN axis.

Nanopore sequencing of the glucocerebrosidase (GBA) gene in a New Zealand Parkinson's disease cohort.

INTRODUCTION: Bi-allelic mutations in the gene for glucocerebrosidase (GBA) cause Gaucher disease, an autosomal recessive lysosomal storage disorder. Gaucher disease causing GBA mutations in the heterozygous state are also high risk factors for Parkinson's disease (PD). GBA analysis is challenging due to a related pseudogene and structural variations (SVs) that can occur at this locus. We have applied and refined a recently developed nanopore DNA sequencing method to analyze GBA variants in a clinically assessed New Zealand longitudinal cohort of PD. METHOD: We examined amplicons encompassing the coding region of GBA (8.9 kb) from 229 PD cases and 50 healthy controls using the GridION nanopore sequencing platform, and Sanger validation. RESULTS: We detected 23 variants in 21 PD cases (9.2% of patients). We detected modest PD risk variant p.N409S (rs76763715) in one case, p.E365K (rs2230288) in 12 cases, and p.T408 M (rs75548401) in seven cases, one of whom also had p.E365K. We additionally detected the possible risk variants p.R78C (rs146774384) in one case, p.D179H (rs147138516) in one case which occurred on the same haplotype as p.E365K, and one novel variant c.335C > T or p.(L335 = ), that potentially impacts splicing of GBA transcripts. Additionally, we found a higher prevalence of dementia among patients with GBA variants. CONCLUSION: This work confirmed the utility of nanopore sequencing as a high-throughput method to identify known and novel GBA variants, and to assign precise haplotypes. Our observations may contribute to improved understanding of the effects of variants on disease pathogenesis, and to the development of more targeted treatments.

Optogenetic stimulation: Understanding memory and treating deficits.

Technology allowing genetically targeted cells to be modulated by light has revolutionized neuroscience in the past decade, and given rise to the field of optogenetic stimulation. For this, non-native, light activated proteins (e.g., channelrhodopsin) are expressed in a specific cell phenotype (e.g., glutamatergic neurons) in a subset of central nervous system nuclei, and short pulses of light of a narrow wavelength (e.g., blue, 473 nm) are used to modulate cell activity. Cell activity can be increased or decreased depending on which light activated protein is used. We review how the greater precision provided by optogenetics has transformed the study of neural circuits, in terms of cognition and behavior, with a focus on learning and memory. We also explain how optogenetic modulation is facilitating a better understanding of the mechanistic underpinnings of some neurological and psychiatric conditions. Based on this research, we suggest that optogenetics may provide tools to improve memory in neurological conditions, particularly diencephalic amnesia and Alzheimer's disease.

Parkinson's in the oldest old: Impact on estimates of future disease burden.

BACKGROUND: Traditionally the risk of Parkinson's has been considered to increase monotonically with age, although there is evidence that prevalence and incidence may decrease in the oldest old. To examine this further we estimated the national prevalence and incidence of Parkinson's in New Zealand, using drug-tracing methods, to examine the relationship of Parkinson's with sex and age up to 100+. METHODS: Information on Parkinson's-related medications was extracted from the national pharmaceutical database of community-dispensed medications from 2005 to 2014. Diagnoses for a large subset of individuals were independently determined through national mortality and hospital admissions datasets. We used a Bayesian model, accommodating diagnostic uncertainty and bias, to estimate the number of people with Parkinson's. RESULTS: The 2013 prevalence of Parkinson's in New Zealand was 210 per 100 000 population (95% uncertainty interval 208-212) with age-standardized prevalence rates higher for males (ratio 1.6:1). Incidence was 31 per 100 000 person-years (95% uncertainty interval 30-32), also higher in males (ratio 1.8:1). Incidence and prevalence by age increased exponentially until 75 years, peaked at 85 years, and then dropped sharply. CONCLUSIONS: The prevalence of Parkinson's in New Zealand is expected to double over a 25-year period but then increase at a slower rate due to the drop-off in prevalence and incidence in the oldest old. The findings suggest that Parkinson's disease is not an aging-dependent but an age-dependent disorder.

Effects of thalamic lesions on repeated relearning of a spatial working memory task.

Anterior thalamic (ATN) dysfunction produces memory deficits in rats and humans. The current study shows that, with a substantial delay between post-surgery tests, controls show repeated relearning on a spatial working memory task whereas rats with neurotoxic ATN lesions showed repeated relearning deficits. Rats were pre-trained to criterion, but not over trained, on the spatial task. ATN lesions produced the expected spatial memory and relearning deficits about two weeks post-surgery and again either one or 15 weeks later. Control rats also showed forgetting post-surgery and after a 15 week break, relearning the task on each occasion. Controls with only a 1 week break before their final re-test showed negligible forgetting. Thus, a short break between re-tests replicated previous findings with ATN lesions, but a long break allows repeated comparison of rates of learning from a common starting point in sham and ATN-lesioned animals, providing a useful paradigm for future testing of pro-cognitive treatments.

C-type natriuretic peptide in Parkinson's disease: reduced secretion and response to deprenyl.

C-type natriuretic peptide (CNP) is a neurotrophic factor widely expressed in the central nervous system including the basal ganglia, limbic system and hypothalamus. Nothing is known of CNP's role in the human brain but in rodents CNP promotes axon growth and branching, and interacts with dopaminergic function in models of addiction. Because preliminary evidence showed reduced levels in Parkinson's disease (PD), we examined concentrations of CNP peptides in cerebrospinal fluid (CSF) in 146 PD patients from the DATATOP study to determine changes over time in relation to medication status and cognitive function. CNP and an aminoterminal product of proCNP (NTproCNP) were measured in extracts from stored CSF by radioimmunoassay. CSF samples were obtained twice-at enrolment and at the study's endpoint (requirement for levodopa treatment) after treatment with placebo or deprenyl. At enrolment, median baseline concentration of CSF NTproCNP (776 pmol/L, n = 146) was significantly lower than that in a reference group without neurological disorder (1,010 pmol/L, p < 0.001). Concentrations declined significantly during placebo (p = 0.02) and lower values at enrolment were associated with more rapid functional decline (p < 0.01). In contrast, deprenyl-a treatment which delayed the need for levodopa-nullified the time-dependent decline in CSF NTproCNP. In conclusion subnormal CSF NTproCNP which declines with time and associates with increasing functional disability implicates CNP in PD. Concordant clinical and peptide responses to deprenyl suggest that some of the benefits of monoamine oxidase inhibitors in PD are mediated by preserving tissue CNP activity.

The MoCA: well-suited screen for cognitive impairment in Parkinson disease.

OBJECTIVE: To establish the diagnostic accuracy of the Montreal Cognitive Assessment (MoCA) when screening externally validated cognition in Parkinson disease (PD), by comparison with a PD-focused test (Scales for Outcomes in Parkinson disease-Cognition [SCOPA-COG]) and the standardized Mini-Mental State Examination (S-MMSE) as benchmarks. METHODS: A convenience sample of 114 patients with idiopathic PD and 47 healthy controls was examined in a movement disorders center. The 21 patients with dementia (PD-D) were diagnosed using Movement Disorders Society criteria, externally validated by detailed independent functional and neuropsychological tests. The 21 patients with mild cognitive impairment (PD-MCI) scored 1.5 SD or more below normative data in at least 2 measures in 1 of 4 cognitive domains. Other patients had normal cognition (PD-N). RESULTS: Primary outcomes using receiver operating characteristic (ROC) curve analyses showed that all 3 mental status tests produced excellent discrimination of PD-D from patients without dementia (area under the curve [AUC], 87%-91%) and PD-MCI from PD-N patients (AUC, 78%-90%), but the MoCA was generally better suited across both assessments. The optimal MoCA screening cutoffs were <21/30 for PD-D (sensitivity 81%; specificity 95%; negative predictive value [NPV] 92%) and <26/30 for PD-MCI (sensitivity 90%; specificity 75%; NPV 95%). Further support that the MoCA is at least equivalent to the SCOPA-COG, and superior to the S-MMSE, came from the simultaneous classification of the 3 PD patient groups (volumes under a 3-dimensional ROC surface, chance = 17%: MoCA 79%, confidence interval [CI] 70%-89%; SCOPA-COG 74%, CI 62%-86%; MMSE-Sevens item 56%, CI 44%-68%; MMSE-World item 62%, CI 50%-73%). CONCLUSIONS: The MoCA is a suitably accurate, brief test when screening all levels of cognition in PD.

Effects of acute tryptophan depletion on neuropsychological and motor function in Parkinson's disease.

Interactions between the 5-HT system and the dopaminergic system and cholinergic system may be important in determining cognitive function and motor function in Parkinson's disease (PD). Previous studies have shown effects of reducing serotonin function, by acute tryptophan depletion (ATD), on neuropsychological function. In particular, an adverse effect on verbal memory has been demonstrated. This study compared with the effects of ATD on cognitive and motor function in PD and healthy control subjects. The effects of ATD were investigated in a double-blind, placebo-controlled, counterbalanced, cross-over, randomised design in 20 patients with PD and 35 healthy controls matched for age, gender and premorbid IQ. There was a differential group effect of ATD on global cognitive function whereby the mean score on the modified mini mental state examination during ATD was lower than placebo in PD but higher in controls. There was a similar pattern of effects on verbal recognition. In a visual recognition task, ATD improved performance in the PD but not in the control group. In terms of psychomotor speed, there was also a group-specific effect with reduced latency of response during ATD in the PD group but increased latency in the control group. ATD has subtle neuropsychological effects, which differ significantly between PD and healthy control subjects. This suggests that the dopaminergic and cholinergic deficit of PD significantly modulates the effects of serotonin depletion, resulting in positive effects in some domains. Further investigation on the effects of specific serotonin antagonists may be merited in PD.

The effects of acute tryptophan depletion on mood in patients with Parkinson's disease and the healthy elderly.

Reduced serotonergic tone may be a compensatory adaptation to reduced dopaminergic activity in Parkinson's disease (PD) and may result in vulnerability to depression. To test this hypothesis this study examined the effects of serotonin depletion, using the technique of acute tryptophan depletion (ATD) in PD. The effects of ATD were investigated in a double-blind, placebo-controlled, counterbalanced, cross-over, randomised design, in 20 patients with PD and 32 healthy controls matched for age, gender and pre-morbid IQ. The primary outcome was change in scores on a modified Montgomery-Asberg Depression Rating Scale (MADRS). ATD resulted in a small but statistically significant increase in score on the MADRS, but there was no effect specific to the PD group. The results do not support the hypothesis that low serotonergic tone results in vulnerability to depression in PD and are in accord with an earlier study using the same technique in PD.

Cognitive characteristics associated with mild cognitive impairment in Parkinson's disease.

BACKGROUND: Cognitive deficits are common in Parkinson's disease (PD), but the range of deficits is variable. The aim of this study was to identify different cognitive subgroups associated with PD. METHODS: A broad range of neuropsychological measures and cognitive domains were used in a cluster analysis to identify subgroups of patients. RESULTS: Three subgroups of patients were identified. Compared to controls, one PD subgroup showed no or minimal cognitive impairment (PD-NCI), a second group showed a variable or uncertain pattern of mild to severe cognitive impairments (PD-UCI), and a third group had evidence of severe cognitive impairment across most cognitive domains (mild cognitive impairment; PD-MCI). The subgroups did not differ with regard to age, motor impairment, or disease duration. CONCLUSIONS: Patients with PD are heterogeneous with regard to cognitive presentation and it may be possible to identify patients in the preclinical stage of dementia. The identification of preclinical dementia in PD patients (PD-MCI) provides an opportunity to understand cognitive decline in PD and its progression to dementia.

A profile of neuropsychiatric problems and their relationship to quality of life for Parkinson's disease patients without dementia.

Neuropsychiatric problems are common in Parkinson's disease (PD) but there is little information regarding how they impact on quality of life. PD patients without dementia (49) were assessed for low mood/depression, fatigue, apathy, sleep problems and hallucinations. Measures of quality of life and motor function were also obtained. Over 77% of the patients reported symptoms consistent with one or more neuropsychiatric problems. Low mood/depression, anxiety and the presence of hallucinations predicted poorer quality of life after controlling for motor symptoms. Additional to the motor symptoms, we found that specific neuropsychiatric problems may impact on quality of life for PD patients.

Planning in Parkinson's disease: a matter of problem structure?

Although the Tower of London (TOL) has been extensively used to assess planning ability in patients with Parkinson's disease (PD), the reported presence or extent of any planning deficits has been inconsistent. This may partly be due to the heterogeneity of the TOL tasks used and a failure to consider how structural problem parameters may affect task complexity. In the present study, planning in PD patients was assessed by systematically manipulating TOL problem structure. Results clearly disprove the identity assumption of problems with an equal number of minimum moves. Instead, substantial parts of planning performance were related to more subtle aspects of problem structure, such as subgoaling patterns and goal hierarchy. Planning in PD patients was not impaired in general but was affected when the information provided by the problem states was ambiguous in terms of the sequential order of subgoals, but not by increases in search depth.

Long term psychosocial outcomes after mild head injury in early childhood.

OBJECTIVES: The question of whether any adverse cognitive or psychosocial outcomes occur after mild head injury in early childhood has evoked considerable controversy. This study examined mild head injury before age 10 and potential differences in late childhood/early adolescence as a function of severity of mild injury and age at injury. METHODS: A fully prospective longitudinal design tracked a large birth cohort of children. Confirmed cases of mild head injury before age 10 were divided on the basis of outpatient medical attention (n=64-84) or inpatient observation (hospital overnight; n=26-28 ) and compared with the non-injured remainder of the cohort (reference group; n=613-807). A range of pre-injury and post-injury child and family characteristics were used to control for any potential confounds. Outcome after injury before and after age 5 was also assessed. RESULTS: After accounting for several demographic, family, and pre-injury characteristics, the inpatient but not the outpatient group displayed increased hyperactivity/inattention and conduct disorder between ages 10 to 13, as rated by both mothers and teachers. Psychosocial deficits were more prevalent in the inpatient subgroup injured before age 5. No clear effects were evident for various cognitive/academic measures, irrespective of severity of mild injury or age at injury. CONCLUSIONS: Most cases of mild head injury in young children do not produce any adverse effects, but long term problems in psychosocial function are possible in more severe cases, perhaps especially when this event occurs during the preschool years. The view that all mild head injuries in children are benign events requires revision and more objective measures are required to identify cases at risk.

Effects of lesions to the cerebellar vermis and hemispheres on timing and counting in rats.

The effects of lesions to the cerebellum on numerical and temporal discrimination were examined in rats using a psychophysical choice procedure. Lesions to the cerebellar hemispheres but not the cerebellar vermis produced performance deficits in a numerical discrimination task (2-8 events) and a milliseconds temporal discrimination task (0.2-0.8 s). However, temporal discriminations in the seconds range (2-8 s) were unaffected by either type of lesion. Using W. H. Meck and R. M. Church's (1983) mode-control model of timing and counting, these findings suggest that damage to the cerebellar hemispheres influences a source of constant variability (e.g., switch processes) because constant variability is a prominent source of error during both milliseconds timing and counting but is masked by other sources of variability when timing longer durations (>2 s).

Timing ability and numerical competence in rats.

Counting and timing ability in Wistar rats was tested in 4 psychophysical choice experiments. After training naive rats with discrete sound sequences that confounded time and number, only time gained control of behavior; control by time was stronger and acquired more rapidly after training with separate time- and number-relevant signals. Two nonnumeric cues associated with periodic sequences, temporal ratio and sequence pattern, did not appear to provide the basis for numerical discrimination, as performance was unaffected by a sudden change from periodic signals to signals with unique temporal patterns. Even after highly accurate performance with number, time showed exclusive control of behavior for signals with conflicting time and number cues. This study provides an unequivocal demonstration that rats can count, but they do so according to H. Davis and J. Memmott's (1983) "last resort" hypothesis.

Both anteromedial and anteroventral thalamic lesions impair radial-maze learning in rats.

Disruption to the anterior thalamus (AT) may be an important factor in diencephalic amnesia. Rats with small lesions of the anteromedial (AM) or anteroventral (AV) nucleus showed persistent working-memory and reference-memory deficits in a 12-arm radial maze, although they were comparable to controls during the early part of training. The only activity difference in the maze was that lesioned rats failed to run more slowly when revisiting a baited arm. For all groups, both working and reference memory were impaired after extramaze cues were removed; removal of intramaze cues further impaired performance relative to the original conditions. These findings suggest the AT makes a distinct contribution to mnemonic functions, probably as part of an integrated system involving limbic cortex and the hippocampal formation, and that AT lesions produce a general rather than a specific deficit in spatial or working memory.

Effects of selegiline (deprenyl) on cognition in early Parkinson's disease.

The influence of selegiline (5 mg b.i.d.) on cognition of 20 levodopanaive patients with early Parkinson's disease (PD) was examined in an 8-week, randomized, placebo-controlled, double-blind trial. Clinical evaluations and cognitive tests were administered at baseline and at 8 weeks; patients with PD who received placebo were also examined 8 weeks after subsequent selegiline treatment. By comparison with non-PD controls, patients with PD were impaired on the Wisconsin card sorting task and on the advanced progressive matrices test, but not in terms of their performance on the Rivermead behavioral memory test or on the rod (spatial) orientation test. Selegiline improved scores on the mentation/mood part and the activities of daily living part of the Unified Parkinson's Disease Rating Scale, but it did not improve motor scores on this test, nor did it have clear effects on the specific neuropsychological measures that were examined.

Behavioural consequences of frontal cortex grafts and enriched environments after sensorimotor cortex lesions.

Past studies have experienced difficulty in achieving graft survival and behavioural recovery after sensorimotor cortex lesions. In the present work, adult female rats trained preoperatively to cross a narrow beam for food reward were maintained in standard group cages or an enriched environment, commencing one week after a unilateral lesion. One month post-lesion, half of these rats received multiple suspension grafts of (E20) fetal frontal cortex, placed adjacent to the lesion cavity, and 8 days later recovery of beam-walking skills was examined for a six-week period. The grafts survived in all cases with an appropriate lesion, a notable result given the one month lesion-graft delay, but graft volume was not influenced by postoperative environment. The substantial lesion-induced deficits evident just prior to differential housing showed a marked reduction by the start of post-graft testing, but relative to intact controls a persistent deficit in foot slip errors occurred in all lesion groups. Irrespective of graft status, postoperative enrichment prevented the occurrence of severe foot slips, especially early in retraining. The frontal grafts, however, enhanced beam-walking recovery by reducing the overall frequency of foot slips on early post-grafting sessions, an effect we suggest is related to graft-derived trophic influences, but this measure was not significantly improved by postoperative enrichment.

Behavioral effects of basal forebrain grafts after dorsal septo-hippocampal pathway lesions.

There are many reports that basal forebrain grafts ameliorate behavioral impairments produced by dorsal septo-hippocampal pathway lesions, but several studies have either found that this recovery may be unrelated to concomitant restitution of cholinergic markers, may be modest and depend on certain experimental conditions or instead that grafts may actually exacerbate lesion-induced impairments. In this study, rats received one of three lesions of the dorsal septo-hippocampal pathways or a sham lesion, at 32 days of age, and intrahippocampal basal forebrain grafts or the vehicle control 10 days later. In grafted rats with total aspirative lesion of the fimbria-fornix, there was a substantial AChE-positive hippocampal reinnervation but no improvement of the severe lesion-induced spatial learning deficits, either reference memory or working memory, whether tested at 1 or 5 months post-grafting. In rats with bilateral medial fimbria lesions, grafts were successful, normal in appearance and produced substantial hippocampal cholinergic reinnervation; relative to non-grafted counterparts, however, grafted medial fimbria rats showed an early reference memory impairment and a persistent exacerbation of a working memory deficit. Exacerbation of learning impairments was also apparent in grafted rats with partial hippocampal denervation due to lesion of the cingulate and adjacent cortex above the fimbria-fornix. Nonetheless, basal forebrain grafts normalised general activity in these lesion groups, irrespective of whether the lesion-induced change was an increase or a decrease relative to controls. Graft-derived lesion groups, irrespective of whether the lesion-induced change was an increase or a decrease relative to controls. Graft-derived AChE-positive innervation was more marked than expected in both grafted cingulate-lesioned rats and grafted sham-lesioned rats, while control grafts of fetal cortex (above the septum) produced little or no AChE-positive innervation. Size of basal forebrain grafts, originally 3 microliters at two dorsal sites per hippocampus, increased markedly from rostral to caudal dorsal hippocampus in all groups but did not differ significantly across grafted groups, even with respect to non-lesioned rats. This study adds further evidence that basal forebrain grafts, successful with respect to cholinergic reinnervation, do not always enhance cognitive functions in rat hippocampal lesion models, and confirms that these grafts may have adverse effects after partial septo-hippocampal system lesions. It is important to attend to both the potential negative and positive effects of neural grafts.