Genipin-crosslinked fibrin seeded with oxidized alginate microbeads as a novel composite biomaterial strategy for intervertebral disc cell therapy.

Discectomy procedures alleviate disability caused by intervertebral disc (IVD) herniation, but do not repair herniation-induced annulus fibrosus (AF) defects. Cell therapy shows promise for IVD repair, yet cell delivery biomaterials capable of sealing AF defects and restoring biomechanical function have poor biological performance. To balance the biomechanical and biological demands of IVD cell delivery biomaterials, we engineered an injectable composite biomaterial using cell-laden, degradable oxidized alginate (OxAlg) microbeads (MBs) to deliver AF cells within high-modulus genipin-crosslinked fibrin (FibGen) hydrogels (FibGen + MB composites). Conceptually, the high-modulus FibGen would immediately stabilize injured IVDs, while OxAlg MBs would protect and release cells required for long-term healing. We first showed that AF cells microencapsulated in OxAlg MBs maintained high viability and, upon release, displayed phenotypic AF cell morphology and gene expression. Next, we created cell-laden FibGen + MB composites and demonstrated that OxAlg MBs functionalized with RGD peptides (MB-RGD) minimized AF cell apoptosis and retained phenotypic gene expression. Further, we showed that cell-laden FibGen + MB composites are biomechanically stable and promote extracellular matrix (ECM) synthesis in long-term in vitro culture. Lastly, we evaluated cell-laden FibGen + MB-RGD composites in a long-term bovine caudal IVD organ culture bioreactor and found that composites had low herniation risk, provided superior biomechanical and biological repair to discectomy controls, and retained anabolic cells within the IVD injury space. This novel injectable composite hydrogel strategy shows promise as an IVD cell delivery sealant with potentially broad applications for its capacity to balance biomechanical and biological performance.

More unaffected first-degree relatives of essential tremor cases have mild cognitive deficits than age-matched controls.

BACKGROUND: In numerous case-control studies, essential tremor (ET) has been associated with cognitive impairment. ET is often familial. However, cognitive impairment has not been studied in family members of ET cases. Endophenotypes are measurable clinical characteristics that may be present in individuals with increased risk for disease; as such, they may be present before disease onset. We administered a global cognitive screen to first-degree relatives of ET cases (FD-ET) and age-matched controls (Co). METHODS: We administered the Montreal Cognitive Assessment (MoCA) to 156 FD-ET and 73 Co, none of whom were diagnosed with ET or reported tremor. MoCA <26 was considered suggestive of cognitive impairment. RESULTS: FD-ET and Co were similar with respect to age (60.1 ±â€¯8.3 vs. 60.9 ±â€¯7.4 years) and numerous demographic factors. FD-ET and Co also had similar MoCA scores; however, 34 of 156 (21.8%) FD-ET had a MoCA score <26 vs only 5 (6.9%) of 73 Co (p = 0.004). In a univariate logistic regression model, FD-ET were 3.79 times more likely to have a low (<26) MoCA than were Co (odds ratio = 3.79, p = 0.008). In a multivariate logistic regression model, adjusting for age and other covariates, FD-ET were 4.83 times more likely to have a low MoCA than were Co (odds ratio = 4.83, p = 0.003). CONCLUSION: More FD-ET had low MoCA scores when compared with Co. These data provide additional support for the scientific notions that (1) cognitive difficulties are a disease-associated feature of ET and (2) there may be a pre-tremor phase of illness in ET.

Transient, Isolated Head Tremor in "Unaffected" Individuals: Is Essential Tremor an Even More Prevalent Disease Than We Suppose?

Background: Mild and transient head tremor may sometimes be observed in otherwise tremor-free relatives of essential tremor (ET) cases, although its prevalence is unclear. A diagnostic question is whether this transient, isolated head tremor, often observed as no more than a wobble, is an early manifestation of ET or whether it is a normal finding. A direct comparison with controls is needed. Methods: Two hundred and forty-one first-degree relatives of ET cases (FD-ET) and 77 spousal controls (Co) were enrolled in a study of ET. Each underwent a detailed evaluation that included a tremor history and videotaped neurological examination. None of the enrollees reported tremor, had a prior diagnosis of ET, or had significant tremor on screening spirals. All videotaped examinations were initially reviewed by a movement disorder neurologist blinded to subject type, and among those with head tremor on examination, co-reviewed by two additional movement disorders neurologists. Results: Twenty-six (10.8, 95% Confidence interval [CI] = 7.5-15.3%) of 241 FD-ET vs. 2 (2.6, 95% CI = 0.7-9.0%) of 77 Co had isolated, transient head tremor (odds ratio = 4.54, 95% CI = 1.05-19.57, p = 0.04). No enrollee had significant upper extremity tremor and none met inclusion criteria for ET based on the presence of upper extremity tremor. With one exception, head tremor occurred during or after phonation. It was always transient (generally a single back and forth wobble) and rare (observed briefly on one or two occasions during the videotaped examination) and had a faster frequency, lower amplitude and a different quality than voluntary head shaking. Conclusion: The basis for the observed isolated head tremor is unknown, but it could be an early feature of ET in ET families.Indeed, one-in-ten otherwise unaffected first-degree relatives of ET cases exhibited such tremor. To a far lesser extent it was also observed in "unaffected" controls. In both, it is likely a sign of early, emerging, undiagnosed ET, although follow-up studies are needed to confirm this. If it were ET, it would indicate that the prevalence of ET may be considerably higher than previously suspected.

Caffeine Consumption in First-Degree Relatives of Essential Tremor Cases: Evidence of Dietary Modification Before Disease Onset.

BACKGROUND: Caffeine can exacerbate tremor. Reducing caffeine intake or switching to decaffeinated beverages can lessen tremor. Unaffected relatives of essential tremor (ET) cases often have mild, subclinical tremor. One question is whether the coffee and tea consumption pattern in these individuals differs from that of controls (Co). METHODS: We ascertained the patterns of coffee and tea intake using a structured questionnaire, and compared the use in unaffected first-degree relatives of ET cases (FD-ET) to the use in age-matched Co. Three measures of relative caffeinated coffee + tea to decaffeinated coffee + tea were constructed. Caffeine index 1 = (cups of caffeinated coffee + tea) - (cups of decaffeinated coffee + tea) consumed on the day of evaluation. Caffeine index 2 = (cups of caffeinated coffee + tea) - (cups of decaffeinated coffee + tea) consumed in a typical month. The percentage of coffee and tea that was caffeinated in a typical month was also calculated. RESULTS: There were 263 individuals (190 FD-ET, 73 Co). Caffeine index 1 in FD-ET was less than 1-half that of Co (p = 0.001). Caffeine index 2 was similarly lower in FD-ET than Co (p = 0.027). The percentage of coffee and tea that was caffeinated in a typical month was also significantly lower in FD-ET than Co (p = 0.018). CONCLUSION: The balance of caffeinated to decaffeinated beverages is different in FD-ET than Co. These data raise several intriguing questions. Among these is whether relatives of ET cases modify their caffeine consumption before disease onset.

Unaffected first-degree relatives of essential tremor cases have more imbalance than age-matched control subjects.

BACKGROUND: Endophenotypes are measurable clinical characteristics that may be present in individuals with increased risk for disease (e.g., unaffected family members). Endophenotypes are useful; they may clarify diagnosis in genetic studies and foster the development of animal models. In recent years, problems with balance and mild gait ataxia have been associated with essential tremor (ET). We compared gait and balance of first-degree relatives of ET cases (FD-ET) to that of age-matched controls (Co). METHODS: One-hundred-ninety FD-ET and 68 Co, none of whom reported tremor or were diagnosed with ET, underwent a standardized assessment of gait and balance. RESULTS: FD-ET reported more near-falls in the past year (p = 0.015) and lower balance confidence according to the Activities of Balance Confidence (ABC-6) Scale (p = 0.03). The specific ABC-6 items for which FD-ET reported lower balance confidence than Co were being bumped into by people while walking (p = 0.006) and walking outside on icy sidewalks (p = 0.007). On videotaped neurological examination, FD-ET were able to stand in the tandem position for fewer seconds than were Co (p = 0.048). The differences between FD-ET and Co, although statistically significant, were clinically mild. CONCLUSION: FD-ET reported more near-falls in the past year and a reduction in balance confidence; additionally, ability to maintain tandem stance was impaired compared to Co. These data suggest a more pervasive abnormality of cerebellar dysfunction than previously conceived, extending beyond ET cases themselves and manifesting in mild form in their unaffected family members.

Comparative Burden of Subclinical Tremor in a Cohort of Normal Individuals Stratified by Familial Risk for Essential Tremor.

BACKGROUND: The burden of mild (i.e., subclinical) tremor within essential tremor (ET) families is not fully understood. We assessed the burden of mild tremor in a cohort of 287 adults, none of whom reported tremor or were diagnosed with ET. METHODS: We recruited adults in 2 groups based on the familial risk for ET: 244 high-risk individuals (i.e., reporting one or more first-degree relative with ET) and 43 low-risk individuals (i.e., reporting no relatives with ET). Tremor was objectively assessed on 4 hand-drawn spirals (total spiral score = 0-12). Mild tremor was defined using 3 different cut points. RESULTS: The prevalence rates of mild tremor among high-risk individuals ranged from 41.4 to 98.4% and were highly dependent on the cut point. Above a certain threshold (i.e., a total spiral score ≥5), 1-in-5 (i.e., 19.7%) high-risk individuals exhibited mild tremor, whereas no low-risk individuals did. High-risk individuals were 3.09-4.50 times more likely than low-risk individuals to exhibit mild tremor. CONCLUSION: The burden of ET extends beyond the boundaries of the clinically defined disease, and partially expressed forms of ET are abundant in ET families. This fact greatly complicates gene-finding studies and epidemiological studies whose goal is to detect disease-linked associations.