Caregiver Experiences Navigating the Diagnostic Journey in a Rapidly Progressing Dementia.

INTRODUCTION: People with suspected Alzheimer's disease and related dementias (ADRD) and their families experience a burdensome process while seeking a diagnosis. These challenges are problematic in the most common dementia syndromes, but they can be even more distressing in rarer, atypical syndromes such as rapidly progressive dementias (RPDs), which can be fatal within months from onset. This study is an examination of the diagnostic journey experience from the perspective of caregivers of people who died from the prototypic RPD, sporadic Creutzfeldt-Jakob Disease (sCJD). METHODS: eIn this mixed-methods study, qualitative data were drawn from interviews with former caregivers of 12 people who died from sCJD. Chart review data were drawn from research and clinical chart data about the person with sCJD. Data were analyzed by a multidisciplinary research team using qualitative and descriptive statistical analysis. RESULTS: We identified 4 overarching themes that characterized the experience of the diagnostic journey in sCJD: clinician knowledge, clinician communication, experiences of uncertainty, and the caregiver as advocate. We also identified 4 phases along the diagnostic journey: recognition, the diagnostic workup, diagnosis, and post-diagnosis. Sub-themes within each phase include struggles to recognize what is wrong, complex processes of testing and referrals, delay and disclosure of diagnosis, and access to resources post-diagnosis. CONCLUSIONS: Findings suggest that more work is needed to improve clinician diagnostic knowledge and communication practices. Furthermore, caregivers need better support during the diagnostic journey. What we learn from studying sCJD and other RPDs is likely applicable to other more common dementias.

Neurogenesis during Abstinence Is Necessary for Context-Driven Methamphetamine-Related Memory.

Abstinence from methamphetamine addiction enhances proliferation and differentiation of neural progenitors and increases adult neurogenesis in the dentate gyrus (DG). We hypothesized that neurogenesis during abstinence contributes to context-driven drug-seeking behaviors. To test this hypothesis, the pharmacogenetic rat model (GFAP-TK rats) was used to conditionally and specifically ablate neurogenesis in the DG. Male GFAP-TK rats were trained to self-administer methamphetamine or sucrose and were administered the antiviral drug valganciclovir (Valcyte) to produce apoptosis of actively dividing GFAP type 1 stem-like cells to inhibit neurogenesis during abstinence. Hippocampus tissue was stained for Ki-67, NeuroD, and DCX to measure levels of neural progenitors and immature neurons, and was stained for synaptoporin to determine alterations in mossy fiber tracts. DG-enriched tissue punches were probed for CaMKII to measure alterations in plasticity-related proteins. Whole-cell patch-clamp recordings were performed in acute brain slices from methamphetamine naive (controls) and methamphetamine experienced animals (+/-Valcyte). Spontaneous EPSCs and intrinsic excitability were recorded from granule cell neurons (GCNs). Reinstatement of methamphetamine seeking enhanced autophosphorylation of CaMKII, reduced mossy fiber density, and induced hyperexcitability of GCNs. Inhibition of neurogenesis during abstinence prevented context-driven methamphetamine seeking, and these effects correlated with reduced autophosphorylation of CaMKII, increased mossy fiber density, and reduced the excitability of GCNs. Context-driven sucrose seeking was unaffected. Together, the loss-of-neurogenesis data demonstrate that neurogenesis during abstinence assists with methamphetamine context-driven memory in rats, and that neurogenesis during abstinence is essential for the expression of synaptic proteins and plasticity promoting context-driven drug memory.SIGNIFICANCE STATEMENT Our work uncovers a mechanistic relationship between neurogenesis in the dentate gyrus and drug seeking. We report that the suppression of excessive neurogenesis during abstinence from methamphetamine addiction by a confirmed phamacogenetic approach blocked context-driven methamphetamine reinstatement and prevented maladaptive changes in expression and activation of synaptic proteins and basal synaptic function associated with learning and memory in the dentate gyrus. Our study is the first to demonstrate an interesting and dysfunctional role of adult hippocampal neurogenesis during abstinence to drug-seeking behavior in animals self-administering escalating amounts of methamphetamine. Together, these results support a direct role for the importance of adult neurogenesis during abstinence in compulsive-like drug reinstatement.

Developing neuropalliative care for sporadic Creutzfeldt-Jakob Disease.

We aimed to identify targets for neuropalliative care interventions in sporadic Creutzfeldt-Jakob disease by examining characteristics of patients and sources of distress and support among former caregivers. We identified caregivers of decedents with sporadic Creutzfeldt-Jakob disease from the University of California San Francisco Rapidly Progressive Dementia research database. We purposively recruited 12 caregivers for in-depth interviews and extracted associated patient data. We analysed interviews using the constant comparison method and chart data using descriptive statistics. Patients had a median age of 70 (range: 60-86) years and disease duration of 14.5 months (range 4-41 months). Caregivers were interviewed a median of 22  (range 11-39) months after patient death and had a median age of 59 (range 45-73) years. Three major sources of distress included (1) the unique nature of sporadic Creutzfeldt-Jakob disease; (2) clinical care issues such as difficult diagnostic process, lack of expertise in sporadic Creutzfeldt-Jakob disease, gaps in clinical systems, and difficulties with end-of-life care; and (3) caregiving issues, including escalating responsibilities, intensifying stress, declining caregiver well-being, and care needs surpassing resources. Two sources of support were (1) clinical care, including guidance from providers about what to expect and supportive relationships; and (2) caregiving supports, including connection to persons with experience managing Creutzfeldt-Jakob disease, instrumental support, and social/emotional support. The challenges and supports described by caregivers align with neuropalliative approaches and can be used to develop interventions to address needs of persons with sporadic Creutzfeldt-Jakob disease and their caregivers.

Voluntary wheel running during adolescence distinctly alters running output in adulthood in male and female rats.

Adult female rats show greater running output compared with age-matched male rats, and the midbrain dopaminergic system may account for behavioral differences in running output. However, it is unknown if the lower running output in adult males can be regulated by wheel running experience during adolescence, and whether wheel running experience during adolescence will diminish the sex differences in running output during adulthood. We therefore determined and compared the exercise output in adult male and female rats that either had initiated voluntary wheel running only during adulthood or during adolescence. Our results demonstrate that running output in adult males were significantly higher when running was initiated during adolescence, and this higher running output was not significantly different from females. Running output did not differ during adulthood in females when wheel running was initiated during adolescence or during adulthood. Higher running output in females was associated with reduced expression of tyrosine hydroxylase and hyperactivation of calcium/calmodulin-dependent protein kinase II (CaMKII) in the dorsal striatum. Notably, running during adolescence-induced higher exercise output in adult males was associated with hyperactivation of CaMKII in the dorsal striatum, indicating a mechanistic role for CaMKII in running output. Together, the present results indicate sexually dimorphic adaptive biochemical changes in the dorsal striatum in rats that had escalated running activity, and highlight the importance of including sex as a biological variable in exploring neuroplasticity changes that predict enhanced exercise output in a voluntary physical activity paradigm.

In vivo reduction of striatal D1R by RNA interference alters expression of D1R signaling-related proteins and enhances methamphetamine addiction in male rats.

This study sought to determine if reducing dopamine D1 receptor (D1R) expression in the dorsal striatum (DS) via RNA-interference alters methamphetamine self-administration. A lentiviral construct containing a short hairpin RNA (shRNA) was used to knock down D1R expression (D1RshRNA). D1RshRNA in male rats increased responding for methamphetamine (i.v.) under a fixed-ratio schedule in an extended access paradigm, compared to D1R-intact rats. D1RshRNA also produced a vertical shift in a dose-response paradigm and enhanced responding for methamphetamine in a progressive-ratio schedule, generating a drug-vulnerable phenotype. D1RshRNA did not alter responding for sucrose (oral) under a fixed-ratio schedule compared to D1R-intact rats. Western blotting confirmed reduced D1R expression in methamphetamine and sucrose D1RshRNA rats. D1RshRNA reduced the expression of PSD-95 and MAPK-1 and increased the expression of dopamine transporter (DAT) in the DS from methamphetamine, but not sucrose rats. Sucrose density gradient fractionation was performed in behavior-naïve controls, D1RshRNA- and D1R-intact rats to determine the subcellular localization of D1Rs, DAT and D1R signaling proteins. D1Rs, DAT, MAPK-1 and PSD-95 predominantly localized to heavy fractions, and the membrane/lipid raft protein caveolin-1 (Cav-1) and flotillin-1 were distributed equally between buoyant and heavy fractions in controls. Methamphetamine increased localization of PSD-95, Cav-1, and flotillin-1 in D1RshRNA and D1R-intact rats to buoyant fractions. Our studies indicate that reduced D1R expression in the DS increases vulnerability to methamphetamine addiction-like behavior, and this is accompanied by striatal alterations in the expression of DAT and D1R signaling proteins and is independent of the subcellular localization of these proteins.

Sex Differences in Context-Driven Reinstatement of Methamphetamine Seeking is Associated with Distinct Neuroadaptations in the Dentate Gyrus.

The present study examined differences in operant responses in adult male and female rats during distinct phases of addiction. Males and females demonstrated escalation in methamphetamine (0.05 mg/kg, i.v.) intake with females showing enhanced latency to escalate, and bingeing. Following protracted abstinence, females show reduced responses during extinction, and have greater latency to extinguish compared with males, indicating reduced craving. Females demonstrated lower context-driven reinstatement compared to males, indicating that females have less motivational significance to the context associated with methamphetamine. Whole-cell patch-clamp recordings on dentate gyrus (DG) granule cell neurons (GCNs) were performed in acute brain slices from controls and methamphetamine experienced male and female rats, and neuronal excitability was evaluated from GCNs. Reinstatement of methamphetamine seeking reduced spiking in males, and increased spiking in females compared to controls, demonstrating distinct neuroadaptations in intrinsic excitability of GCNs in males and females. Reduced excitability of GCNs in males was associated with enhanced levels of neural progenitor cells, expression of plasticity-related proteins including CaMKII, and choline acetyltransferase in the DG. Enhanced excitability in females was associated with an increased GluN2A/2B ratio, indicating changes in postsynaptic GluN subunit composition in the DG. Altered intrinsic excitability of GCNs was associated with reduced mossy fiber terminals in the hilus and pyramidal projections, demonstrating compromised neuroplasticity in the DG in both sexes. The alterations in excitability, plasticity-related proteins, and mossy fiber density were correlated with enhanced activation of microglial cells in the hilus, indicating neuroimmune responses in both sexes. Together, the present results indicate sexually dimorphic adaptive biochemical changes in excitatory neurotransmitter systems in the DG and highlight the importance of including sex as a biological variable in exploring neuroplasticity and neuroimmune changes that predict enhanced relapse to methamphetamine-seeking behaviors.

Hippocampal neural progenitor cells play a distinct role in fear memory retrieval in male and female CIE rats.

Adult male and female GFAP-TK transgenic rats experienced six weeks of chronic intermittent ethanol vapor inhalation (CIE). During the last week of CIE, a subset of male and female TK rats were fed with Valcyte to ablate neural progenitor cells (NPCs). Seventy-two hours after CIE cessation, all CIE and age-matched ethanol naïve controls experienced auditory trace fear conditioning (TFC). Twenty-four hours later all animals were tested for cue-mediated retrieval in the fear context. Adult male CIE rats showed a significant burst in NPCs paralleled by reduction in fear retrieval compared to naïve controls and Valcyte treated CIE rats. Adult female CIE rats did not show a burst in NPCs and showed similar fear retrieval compared to naïve controls and Valcyte treated CIE rats, indicating that CIE-mediated impairment in fear memory and its regulation by NPCs was sex dependent. Valcyte significantly reduced Ki-67 and NeuroD labeled cells in the dentate gyrus (DG) in both sexes, demonstrating a role for NPCs in reduced fear retrieval in males. Valcyte prevented adaptations in GluN2A receptor expression and synaptoporin density in the DG in males, indicating that NPCs contributed to alterations in plasticity-related proteins and mossy fiber projections that were associated with reduced fear retrieval. These data suggest that DG NPCs born during withdrawal and early abstinence from CIE are aberrant, and could play a role in weakening long-term memory consolidation dependent on the hippocampus.