Ward et al.'s recent study on frailty, lifestyle, genetics and dementia risk (1) is a major contribution to the growing multimorbidity approach towards dementia. But it is not clear why the authors exclusively frame their discussion on practical steps to reduce dementia risk around healthy lifestyle. They paradoxically argue that "adherence to national guidelines for healthy lifestyle behaviours is central to dementia risk reduction recommendations," while also recognising that multi-domain lifestyle interventions have a weak evidence base in favour of them. An exclusive focus on lifestyle to achieve reduction of frailty and dementia overlooks social gradients of health, particularly the unequal distribution of access to the kind of safe and stimulating living and working environments in which risk reduction can take place through high-quality stimulation and the absence of stressors like noise and air pollution (2). The authors make no mention of social determinants. People with higher income are more likely to part in lifestyle interventions (3), and focusing exclusively on conscious behavioural change to achieve dementia risk reduction may therefore worsen inequalities in dementia risk (4). Therefore, to address not only dementia risk reduction but also the reduction of health inequities, as well as promoting lifestyle changes, the research community ought to stress the need for action against the social determinants of frailty and dementia (5).

References
1 - Ward DD, et al. Frailty, lifestyle, genetics and dementia risk Journal of Neurology, Neurosurgery & Psychiatry Published Online First: 21 December 2021. doi: 10.1136/jnnp-2021-327396
2 - Daly T. Giving a fairer face to urban space: Progress on the long road to dementia prevention. Int J Geriatr Psychiatry. 2022 Jan;37(1). doi: 10.1002/gps.5657. 
3 - Coley N, et al. Disparities in the participation and adherence of older adults in lifestyle-based multidomain dementia prevention and the motivational role of perceived disease risk and intervention benefits: an observational ancillary study to a randomised controlled trial. Alzheimers Res Ther. 2021 Sep 24;13(1):157. doi: 10.1186/s13195-021-00904-6.
4 - Walsh S, et al. A whole-population approach is required for dementia risk reduction. The Lancet Health Longevity 2022 3(1), E6-E8. doi: 10.1016/S2666-7568(21)00301-9.
5 - Daly T. The vital need for action against the social determinants of frailty. Aging Medicine. 2022 doi: 10.1002/agm2.12195

We read with interest the letter by Bert-Marcaz et al., reporting on a 74-year-old man with vacuole, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome and chronic inflammatory demyelinating polyneuropathy [1]. We agree with the authors’ postulation that the simultaneous onset of the two diseases suggests a potentially causal link between VEXAS and the demyelinating abnormalities they observed on nerve conduction studies and nerve biopsy. We have previously reported a case of a 68-year-old man with VEXAS associated with neurological features, including ophthalmoplegia, sensorineural hearing loss and bilateral vestibulopathy [2]. Our hypothesis for the mechanism of neurological involvement was polycranial neuritis, given that there was no evidence of orbital inflammation on MRI and there was significant improvement with corticosteroids. Neurologists should consider the diagnosis of VEXAS (and other autoinflammatory syndromes of innate immunity) in patients with neurological problems who have (i) unexplained fever and elevated acute phase reactants, especially when there is a remitting and relapsing course, (ii) unexplained multisystem disease, and (iii) no evidence of infection, malignancy or autoimmune (i.e., antibody-mediated) disease.

References:
[1] Bert-Marcaz C, Briantais A, Faucher B, Corazza G, Ebbo M, Attarian S, Delmont E, Fortanier E. Expanding the spectrum of VEXAS syndrome: association with acute-onset CIDP. J Neurol Neurosurg Psychiatry. 2021 Dec 6:jnnp-2021-327949. doi: 10.1136/jnnp-2021-327949
[2] Diprose WK, Jordan A, Anderson NE. Autoinflammatory syndromes in neurology: when our first line of defence misbehaves. Pract Neurol. 2021 Oct 1:practneurol-2021-003031. doi: 10.1136/practneurol-2021-003031

We read with great interest the paper by Yaghi S. et al on the lacunar stroke mechanisms and their therapeutic implications. We would like to highlight that the deficiency of ADA2 (DADA2) is the most common cause of monogenic vasculitis and is also responsible for causing lacunar strokes, but is commonly overlooked [1]. It has an autosomal recessive inheritance and has multi-system involvement: skin, nervous, gastrointestinal and hematological systems being most commonly involved [1]. Children and young adults are most commonly affected with a “polyarteritis nodosa-type” picture with cutaneous involvement, abdominal pains and renal involvement, and mild strokes. The lacunar infarcts are more common in the posterior circulation [2]. Most cases are diagnosed late or go undiagnosed because of lack of knowledge about this disorder [3, 4].
Patients are treated by immunosuppressants with anti-tumour necrosis factor (TNF) agents and usually adalimumab is the first line agent. Early diagnosis and treatment lead to favorable treatment response.

References:
1. Meyts I, Aksentijevich I. Deficiency of Adenosine Deaminase 2 (DADA2): Updates on the Phenotype, Genetics, Pathogenesis, and Treatment. Journal of Clinical Immunology (2018) 38: 569-578
2. Geraldo AF, Carosi R, Tortora D et al. Widening the Neuroimaging features of Adenosine Deaminase 2 Deficiency. American Journal of Neuroradiology. February 2021
3. Sharma A, Agarwal A, Srivastava MVP, et al. Hypertension with recurrent focal deficits. Pract Neurol 2021;0:1-5
4. Babtiwale S, Vishnu VY, Garg A, et al. Young stroke and systemic manifestations: Deficiency of Adenosine Deaminase-2 (DADA-2). Annals of Indian Academy of Neurology 2020. DOI: 10.4103/aian.AIAN_657_20

Thyroid hormones play a role in the development and function of virtually all human cells, including maturation of olfactory neurons. The clinical observation that patients with hypothyroidism can experience disturbances in their sense of smell was first reported more than 60 years ago, and it was subsequently confirmed in both humans and animal models. In vivo animal studies clearly demonstrated that hypothyroidism induced by anti-thyroid drugs administration in mice was associated to variable degrees of anosmia, which however promptly reverted following restoration of euthyroidism by levothyroxine replacement therapy (1).
This latter finding was regarded as the proof that thyroxine, besides its role for correct development of the nervous system would also be involved in the genesis of new olfactory receptor neurons, a process demonstrated to be maintained also in adulthood.
Since the early phase of the ongoing Sars-CoV-2 pandemic, anosmia was identified as a peculiar clinical symptom of COVID-19 being experienced by nearly 80% of the affected patients (2). It is now known that, at least in some cases, COVID-19 course may encompass protracted olfactory dysfunction and development of olphactory bulb atrophy (3). Thus, attention was paid to potential risk factors predicting this long-term sequela. Interestingly, Tsivgoulis et al., recently performed a prospective case–control study aimed at evaluating whether hypothyroidism could be associated to prolonged COVID19-induced hyposmia/anosmia(3). Olfactory function and anosmia were objectively evaluated by the validated Quick Smell Identification Test. Briefly, among patients with a >40days duration of anosmia in the presence of a negative PCR for Sars-CoV-2, a strikingly higher prevalence of hypothyroidism (50% vs 8%; p=0.009) was observed in cases as compared to controls.
More interestingly, hypothyroidism was identified to be significantly and independently associated with higher risk for persistent olfactory dysfunction among patients with COVID-19, even after adjusting for potential confounders such as age and sex. This latter is a relevant point in that it is known that autoimmune thyroid diseases display a strong female gender prevalence, thus the correction for sex further strengthen the findings.
Although the above results were obtained in a rather limited study group, their potential clinical significance should not be neglected in view of their potential utility in the clinical care of the so called “post-COVID-19” syndrome”. However, some considerations should be drawn. Indeed, all of the patients studied by Tsivgoulis et al. were affected by chronic autoimmune thyroiditis (CAT) and were receiving levothyroxine replacement therapy with restoration of euthyroidism as assessed by normal thyroid function tests at study entry.
Thus, a direct role for thyroid hormones on the persistency of olfactory dysfunction would be difficult to be envisaged in these patients. On the other hand, the observation by Tsivgoulis et al. appears to be worth to be further investigated in view of the following aspects.
CAT is the most prevalent human autoimmune disease being the major cause of primary hypothyroidism. Interestingly, among several immune-active molecules, CXCL10 a Th1-oriented chemokine, was identified to play a crucial role in the recruitment and maintenance of lymphocytes sustaining chronic autoimmune inflammation (4). More specifically, patients with CAT either in the hypothyroid phase and in the euthyroid patients under LT4 phase display significantly higher circulating levels of CXCL10 as compared to both healthy controls and non-autoimmune hypothyroid patients (4). As far as COVID-19 is concerned, CXCL10 is currently regarded as a main actor in the so called “immune signature” of COVID-19, which is characterized by increased levels of soluble biomarkers (cytokine and chemokines) involved in the recruitment and activation of several immune cell types (5). Of note, we have previously reported how CXCL10 would play a crucial role in the genesis of olfactory dysfunction in COVID-19 infections. Briefly, following Sars-CoV-2 entrance in the upper respiratory tract, it enters nerve cells, promoting the secretion of CXCL10, which, in turn, recruits immune cells expressing the CXCL10-receptor CXCR3 (2). CXCL10-dependent attraction of T lymphocytes within the CNS would ultimately contribute to the demyelination of the olfactory pathway. Indeed, CXCL10 is a strongly involved chemokine in T cells recruitment within the CNS and T-lymphocytes are crucial effectors in the demyelination process (2). Taking together the above evidences, while highlighting the interesting findings reported by Tsivgoulis et al., we would strongly support the concept that the elevated circulating concentrations of CXCL10 observed in several human autoimmune condition and in particular CAT, rather than hypothyroidism (unless when left untreated) would be the cause of a more prolonged anosmia in COVID-19 patients.

REFERENCES

1. Beard MD, Mackay-Sim A. Loss of sense of smell in adult, hypothyroid mice. Brain Res. 1987;433(2):181-189.
2. Oliviero A, de Castro F, Coperchini F, Chiovato L, Rotondi M. COVID-19 Pulmonary and Olfactory Dysfunctions: Is the Chemokine CXCL10 the Common Denominator? Neuroscientist. 2020:1073858420939033.
3. Tsivgoulis G, Fragkou PC, Karofylakis E, Paneta M, Papathanasiou K, Palaiodimou L, Psarros C, Papathanasiou M, Lachanis S, Sfikakis PP, Tsiodras S. Hypothyroidism is associated with prolonged COVID-19-induced anosmia: a case-control study. J Neurol Neurosurg Psychiatry. 2021.
4. Rotondi M, Chiovato L, Romagnani S, Serio M, Romagnani P. Role of chemokines in endocrine autoimmune diseases. Endocr Rev. 2007;28(5):492-520.
5. Coperchini F, Chiovato L, Ricci G, Croce L, Magri F, Rotondi M. The cytokine storm in COVID-19: Further advances in our understanding the role of specific chemokines involved. Cytokine Growth Factor Rev. 2021.