Which mental health disorder causes gradual deterioration in the patients cognitive functioning?

Covid-19

The worldwide pandemic of coronavirus disease (COVID19)) caused by Severe Acute Respiratory Syndrome-coronavirus-2 (SARDCoV2) has as of mid-September 2020 been responsible for over 30 million disease cases and nearly 1 million fatalities. The United States has the world’s highest case number (>7 million cases) as well as the most recorded deaths (>200,000). Severe illness and death generally result from respiratory complications of SARSCoV2 infection, notably acute respiratory distress syndrome (ARDS), however, the neurological manifestations of COVID19 are an important source of morbidity and mortality (see Ellul et al., 2020;Iadecola et al., 2020;Koralnik & Tyler, 2020;Pezzini A & Padovani, 2020 for review). The exact frequency of neurological complications of COVID19 remain to be determined but appear to be common, especially in hospitalized and more severely ill patients. In a review of over 200 hospitalized patients with COVID19 in Wuhan China, 36% of cases had neurological signs and symptoms (Mao et al, 2020). In another study of patients hospitalized with COVID19-associated ARDS, 84% had neurological signs (Helms et al., 2020).

The major neurological manifestations of COVID19 can be broadly categorized into: (1) those reflecting the effects of systemic illness on the CNS, (2) direct viral invasion of the CNS including encephalitis, and (3) post-infectious presumably immune-mediated syndromes (Koralnik & Tyler, 2020).

The most common effect on the CNS of systemic COVID19 is the development of encephalopathy. This is typically characterized by altered mental status, agitation, and in some cases, a dysexecutive syndrome. It is seen most commonly in severely ill patients often with multi-organ system impairment that can include respiratory failure and hypoxemia, hepatic dysfunction, renal failure, and cardiac or hemodynamic impairment. Many patients have associated co-morbidities including diabetes and hypertension. Patients are often older and male, as these demographic factors are linked to risk of more severe disease. Patients frequently have very elevated markers of inflammation (e.g., HS-CRP, ESR, ferritin) and signs of systemic coagulopathy (e.g., elevated d-dimer). CSF examination is typically normal or may show a mild protein elevation. Virus is not detected in CSF by RT-PCR. The EEG shows either diffuse or anteriorly predominant slowing. MRI may be normal but, in more severe cases, can show diffuse white matter changes, and juxtacortical and callosal petechial micro-hemorrhages (Radmanesh et. al, 2020). It remains to be seen whether aspects of this syndrome are unique for COVID19 or merely reflect the severity and type of organ system dysfunction including the severe hypoxemia and need for prolonged mechanical ventilation.

Patients with COVID19 may develop or even present with acute cerebrovascular disease. Ischemic large vessel strokes, at times in multiple vascular territories, appear to be the most common manifestation, followed in order of decreasing frequency by intracerebral hemorrhage, venous infarctions, and, possibly, vasculitis. The frequency has been reported at between 1-6% in hospitalized patients with the higher percentages seen in more critically ill cases. The group at highest risk appears to be older and more severely ill patients. These individuals frequently have associated vascular disease risk factors including hypertension, diabetes, smoking, dyslipidemia and heart disease. Strokes often occur 1-3 weeks following the onset of COVID19 symptoms. The mechanism is likely due to thrombosis secondary to the associated hyper-coagulable state, and patients may have evidence of thrombosis in multiple organs including the lungs in addition to the CNS. In some reports there has been a high incidence of pro-thrombotic autoantibodies including lupus anticoagulant, anticardiolipin and anti-beta2-glycoprotein-1 antibodies (Beyrouti et al., 2020).

Abstract

Progressive mental deterioration in old age has been recognized and described throughout human history. However, it was not until the early part of the 20th century that a specific neuropathologic change, the neurofibrillary tangle, was identified by Alois Alzheimer in 1906. Alzheimer identified this change at autopsy in the cerebral cortex of a relatively young patient suffering from progressive cognitive decline. Also present were collections of amorphous debris, previously known as ‘miliary foci’ or ‘nodules of neurosclerosis’ and now known as the senile plaque, although these were described in years prior and associated with so-called dementia senilis. Nevertheless, the atypical clinical presentation, especially the young age at onset, justified a new disease, Alzheimer disease (AD). The definition over time was separated into Alzheimer's disease, or the presenile form, and senile dementia of the Alzheimer-type, based on an arbitrary age cut-off of 65. Although these classifications are still sometimes referred to, AD fails to demonstrate either a bimodal age of onset or phenotypic differences. AD is now viewed as a single entity with a prevalence that increases sharply with age. Indeed, 10% of the population older than 65 years and as many as 47% of those older than 85 years may be affected. Prevalence studies project that 114 million people will be affected worldwide by 2050, and 13.2 million of these will be in the United States.

V.A Dementias

Dementias involve cognitive deterioration (e.g., memory decrements and deficits in attention and concentration) and confusion that progress as a function of age. The most common and most widely studied dementia is Alzheimer's disease (AD). This condition remains a focus of extensive contemporary research, and its etiology is far from clear. However, research has indicated several likely etiologic factors, including the abnormal deposition of amyloid plaques around neurons and neuron bundles (neuritic plaques), which form neurofibrillary tangles, and the depletion of ACh particularly in the cortex and hippocampus. Also, it has been shown that M2 and nicotinic ACh receptors are reduced in patients with AD. The latter body of research has led to pharmacologic treatments designed to treat the cholinergic deficits in AD. Perhaps the most widely used agent of this genre is tetrahyroaminoacridine (Tacrine). This is a high-affinity, noncovalent inhibitor of acetylcholinesterase that, by reduction of the enzyme that inhibits ACh activity, increases net cholinergic activity in the brain. Other acetylcholinesterase inhibitors in clinical use are velnacrine, donepezil, and metrifonate. All have the same basic mechanism but differ in their affinities for acetylcholinesterase and metabolism and, therefore, their side effects. A summary of the research has shown that, although not all studies demonstrate effectiveness, the bulk of the evidence indicates that these agents can improve the behavioral and cognitive functions of AD patients to varying degrees.

HURLER'S SYNDROME

Hurler's syndrome is marked by progressive mental deterioration, hepatosplenomegaly, dwarfism, and gargoyle-like faces. Affected children may be large at birth and appear normal but may have inguinal or umbilical hernias. Growth in height may be initially faster than normal, then begins to slow before the end of the first year and often ends around age 3, resulting in a maximum stature of less than 4 feet. Distinct facial features including flat face, depressed nasal bridge, and bulging forehead become evident in the second year. The liver, spleen, and heart are usually enlarged. Children with Hurler's syndrome often die before age 10 from obstructive airway disease, respiratory infections, or cardiac complications.

Although the vertebral bodies appear relatively normal, these patients frequently exhibit a kyphotic deformity resulting from the malformation of at least one vertebral body, usually the twelfth thoracic or the first lumbar (Fig. 6-34). For unknown reasons, a portion of the anterior half of the affected body or bodies fails to ossify, and the ensuing posterior displacement of one vertebral body on the other leads to kyphosis. However, in Hurler's syndrome, the vertebral column does not show the general wedging of the vertebral bodies present in Morquio's syndrome.

Acute Psychological Stress and Exposure to Anticholinesterases Cause Similar Delayed Effects

Posttraumatic stress disorder (PTSD) involves delayed cognitive deterioration, depression, irritability, and persistent deficits in short-term memory, as summarized by Robert Sapolsky in 2003. Stress-induced changes in nervous system structure and function appear in many diverse species, suggesting that they reflect an evolutionarily conserved adaptation to environmental insults. For example, magnetic resonance imaging (MRI) demonstrates reduced hippocampal volume in PTSD patients.

Surprisingly similar effects are often reported years after acute or chronic exposures to cholinesterase inhibitors. The use of the carbamate anticholinesterase (anti-AChE) pyridostigmine during the Gulf War for prophylactic protection under threat of chemical warfare emphasizes the importance of this topic, as does the increasing use of anti-AChE drugs for the treatment of Alzheimer's disease. Table 1 summarizes these reports.

Table 1. Common outcomes of psychological stress and anticholinesterase exposurea

Neurophysiological stress events are initiated by millisecond-long bursts of neurotransmitter release, whereas the long-term, persistent brain changes occur at a very slow pace, sometimes over years. Moreover, stress responses primarily elicit hormonal modulations in peripheral tissues, and ACh controls inflammatory reactions. Yet, it is not clear how this imprints on brain structure and function in a long-delayed manner. Finally, the link between structural and functional properties in the brain itself calls for an in-depth study of the causal relationships leading to these changes.

Alzheimer’s Disease

AD is characterized by progressive neuronal loss, cognitive deterioration, and behavioral changes. Accumulation of amyloid or senile plaques and formation of neurofibrillary tangles are thought to be the major cause of neuronal loss in the AD brain (Selkoe, 2001). Many of the molecules involved in development of AD could modulate neurogenesis; for example, presenilin 1 (PSEN-1) regulates neuronal differentiation (Gadadhar, Marr, & Lazarov, 2011), and soluble amyloid precursor protein α (sAPPα) regulates cell proliferation (Demars, Hollands, Zhao Kda, & Lazarov, 2013). Divergent results in alteration of hippocampal neurogenesis have been reported among different transgenic animal models of AD. This may be due to large variations in genetic mutations of AD models, for example, single gene mutation with single PSEN-1 or PSEN-2 or APP gene mutation, and knock-in or multiple mutations with combinations of the above-noted genes. Varied regimens of bromodeoxyuridine (BrdU) treatment for labeling proliferating cells, genetic background of the mice, and difference in disease stages may contribute to these divergent findings in adult neurogenesis from the literature.

In an animal model with crossing of apolipoprotein (ApoE)-deficient mice to a nestin–green fluorescence protein (GFP) reporter, ApoE deficiency increases early neural progenitor cell proliferation in the DG, but leads to depletion of neural progenitor cells at later time points (Yang, Gilley, Zhang, & Kernie, 2011). In contrast, transgenic mice (PDGF-APPSw, Ind) at 3 months old (at the stage of pre-Aβ deposition) showed an increase in hippocampal cell survival, with similar increases in cell proliferation. Furthermore, increases in survival rate have also been observed when the mice are 12 months old at the stage of post-Aβ deposition (Jin, Galvan, et al., 2004). This is echoed by a study showing a similar increase in neurogenesis in transgenic mice with overexpression of human APP (Sw, Ind) (Lopez-Toledano & Shelanski, 2007).

Contradictory results have been reported in several studies demonstrating decreased neurogenesis in the DG or/and SVZ in different transgenic mice. A significant reduction in proliferation and survival of neural progenitor cells in the hippocampal dentate region was found in 12- to 14-month-old transgenic mice with an overexpressed mutant form of amyloid precursor protein (APP). The in vitro experiment from this study demonstrated an adverse effect of APP on impairing proliferation and differentiation of neural progenitor cells derived from humans and rodents (Haughey et al., 2002). Similarly, the transgenic mouse model with overexpression of APP and PSEN-1 showed a significant decrease in cell proliferation, differentiation, and survival of hippocampal progenitor cells (Verret, Jankowsky, Xu, Borchelt, & Rampon, 2007). A triple transgenic mouse model (3XTg-AD with three mutant genes, including β-amyloid precursor protein, presenilin-1, and tau), showed a significant decrease in hippocampal cell proliferation in association with formation of Aβ plaques and neurons containing Aβ (Rodriguez et al., 2008). In an AD animal model with APPswe KM670/67INL, Ermini et al. (2008) found a decrease in immature neurons at 5 months of the presymptomatic stage, and an increase in proliferative cells at 25 months of the symptomatic stage. These data suggest an age-dependent effect on alteration of hippocampal neurogenesis in this animal model. Increase in neurogenesis at early stages of the disease may possibly be a compensatory mechanism for the early loss of newborn neuron in the DG. However, an overall decrease in neurogenesis was reported at the late stage of AD development. Detailed examination of changes in neurogenesis at different disease stages of AD will shed light on dysregulation in adult neurogenesis and its relationship to cognitive decline in AD.

Several molecules contributing to the neuropathology of AD, such as APP, mutations in ApoE, and PENS1, have been shown to regulate adult neurogenesis. The soluble APP, which is produced by APP cleavage by alpha-secretase, can rescue the age-related decline in NPCs proliferation (Demars et al., 2013). APP may promote neurogenesis by inhibiting the activity of cyclin-dependent kinase 5 and hyperphosphorylation of tau protein (Han et al., 2005). On the other hand, suppression of ApoE promotes proliferation of DG neural progenitor cells (Yang et al., 2011) while ApoE knock-in reduces hippocampal neurogenesis (Li et al., 2009). PENS-1 was reported to regulate neuronal differentiation (Gadadhar et al., 2011). PENS-1 mutation reduces hippocampal neurogenesis because PS1M146V knock-in impairs hippocampal-dependent contextual learning and reduces adult neurogenesis in the DG (Wang, Dineley, Sweatt, & Zheng, 2004). The mutant form of PENS-1 in hu-PS1P117L transgenic mice impairs the survival rate of neural progenitor cells (Wen et al., 2004). Taken together, these data suggest that mutation in ApoE or PENS1 plays an important role in regulating adult neurogenesis during the development of AD.

Adding to the above, dysregulation of γ-aminobutyric acid-ergic (GABAergic) neurons may also contribute to altered adult neurogenesis in AD animals. A decrease in GABAergic interneurons in APoE 4 transgenic mice decreases maturation of newborn neurons, whereas potentiating GABAa receptor restores neurogenesis and dendritic maturation (Li et al., 2009). Therefore, it is speculated that disrupted GABAergic transmission may partly contribute to decreased neurogenesis in these AD transgenic mice.

Similar to the results observed from different animal models of AD, varied findings on hippocampal neurogenesis in the AD brains have been reported in human studies. Increases in hippocampal protein expression of immature and mature neuronal markers including doublecortin (DCX), polysialylated–neural cell adhesion molecule (PSA–NCAM), neurogenic differentiation neuroD, and calbindin have been reported in postmortem tissues from human AD patients (Jin, Peel, et al., 2004). Another study reported no difference in cell proliferation in the DG of AD patients, but an increase in glial and vasculature-abundant area in the granule cell layer (Boekhoorn, Joels, & Lucassen, 2006). Interestingly, Crews et al. (2010) found a decrease in the number of stem cells and immature neurons in the DG.

Type III (juvenile disease)

Type III presents with hepatosplenomegaly followed by gradual mental deterioration any time after the 1st year of life. Initial evidence of neurological involvement may not present until adulthood with supranuclear oculomotor deficits.874 Death occurs in the 2nd–4th decades. Three subtypes are now described: (1) type IIIa is primarily a neurological disorder in adolescence with mild visceral involvement. Death is from slowly progressive neurologic degeneration. Myoclonic seizures are common. (2) Type IIIb has the severe visceral involvement with massive hepatomegaly, oesophageal varices, and severe skeletal involvement. Horizontal supranuclear gaze paresis is the major neurological finding.875 Death is from hepatic or pulmonary complications. Hepatocytes rarely accumulate glucocerebroside because of bile excretion.876 Disease is accelerated by splenectomy. (3) Type IIIc is an unusual variant with calcification of the left-sided heart valves and corneal opacifications.877 Other visceral involvement is mild. In type III, typical complications of portal hypertension occur if cirrhosis develops.878 Hepatic calcification is rare.879 Pulmonary arteriovenous shunts causing hypoxia and cyanosis occur mainly in patients with liver disease.860 There is also infiltration of the lungs by storage cells. The pulmonary shunts as well as the cirrhosis respond to liver transplantation.

Based on the clinical presentation along with the detected genotypic heterogeneity880 have suggested that neuronopathic Gaucher disease is more likely to be a continuum of phenotypes from type II with severe perinatal presentation to mild type III with oculomotor problems.

The gene for acid β-glucosidase is on chromosome 1q21.881,882 Nearly 200 mutations in this gene have been described.883 Although there is a trend for the N370S allele to be associated with milder and non-neuronopathic disease and the L444P allele to be strongly associated with neuronopathic forms, genotype-phenotype correlations are poor,884 implying that if a mutation in the glucocerebrosidase gene is required, other factors play an important role in the manifestation of the disease. Glucocerebrosidase is synthesized on endoplasmic reticulum (ER)-bound polyribosomes and translocated into the ER. Following N-linked glycosylations, it is transported to the Golgi apparatus, from where it is trafficked to the lysosomes. The degree of ER retention and proteasomal degradation and impaired trafficking of the mutants are likely factors that determine disease severity.885,886

A rare variant of Gaucher disease is due to deficiency in small acidic protein activator, saposin C, which is required for optimal hydrolysis of sphingolipids. Mutation in the saposin gene localized to chromosome 10 leads to a variant with a normal acid β-glucosidase enzyme activity which will not be influenced by enzyme therapy.887,888

Diagnosis of Gaucher disease is made by assay of acid β-glucosidase enzyme in white blood cells or cultured fibroblasts. Prenatal diagnosis is by assay of enzyme activity in amniocytes or chorionic villi; polymerase chain reaction can be performed when the genetic mutation is known in both parents.855

Therapy for type I is intravenous recombinant enzyme replacement (ERT) designed to be taken up by the mannose receptor on macrophages,889,890 results in rapid reversal of liver, splenic and bone marrow pathology with clinical improvement, but skeletal disease responds more slowly or may be resistant891,892 the poorest responses were in splenectomized patients, or patients with advanced liver, splenic and bone marrow disease. Splenectomy increases the risk of avascular necrosis which is reduced by starting ERT less than 2 years after diagnosis.893 As an alternative to ERT, substrate reduction using oral miglustat, an inhibitor of glucosylceramide synthase, a key enzyme in glycosphingolipid synthesis, has been shown to produce slower and less robust responses than those obtained with enzyme replacement,894 but it is an effective therapy for the long-term maintenance of patients previously stabilized with enzyme replacement therapy.895 Neurological disease does not respond as the enzyme does not cross the blood–brain barrier, although stabilization or some improvement may be achieved with intravenous treatment in very high dose in type III disease,896 this does not eliminate the neurologic problems that these patients ultimately experience.897

Bone marrow transplantation has been successful but with significant morbidity. Liver transplantation is rarely indicated and must be accompanied by other therapy in order to obtain a cure.898 Chimerism following hepatic transplantation will not reliably produce a cure.899 Gene therapy is being pursued vigorously. A knockout mouse model is available to assist in these studies.900

Histiocytes containing glycocerebroside (Gaucher cells) are dispersed throughout the reticuloendothelial system. A full surface marker study of the splenic storage cells in a case of Gaucher disease has largely substantiated the monocyte/histiocyte nature of Gaucher cells.901 Scanning electron microscopy reveals microvilli, ruffles, ridges and blebs of varying number and shape on their surface.902 In the liver, Kupffer cells and portal macrophages are primarily affected. The distribution may be focal or zonal, with the perivenular zone being mainly affected. The cells, which can measure up to 100 µm in maximum dimension, are lightly stained with eosin, have a faintly striated or crinkled cytoplasm and pyknotic, eccentric or centrally located nuclei (Fig. 4.62). The striations are best demonstrated with the Masson trichrome or a PAS stain (Fig. 4.63). Intense acid phosphatase (Fig. 4.64) and lysozyme activity are found by histochemical or immunohistochemical methods respectively. Gaucher cells are also strongly immunoreactive to anti-KP-1 (Fig. 4.65). They usually contain a small amount of iron that is derived both from ingested erythrocytes and from the labile plasma pool.903 Other staining reactions of Gaucher cells have been reviewed.903,904

Gaucher cells in the liver may enlarge to such an extent that they completely block sinusoidal spaces. They also compress hepatocytes with progressive atrophy and disruption of the hepatic plates. There is a variable increase in the number of reticulin and collagen fibres in the space of Disse. Perisinusoidal fibrosis and mechanical blockage of sinusoidal spaces are presumed to be the cause of portal hypertension, but the pathogenesis of tissue injury in Gaucher disease may be complex, and could also involve activation of stellate cells. Severe fibrosis, with formation of septa and cirrhosis (Fig. 4.66) has been reported.878,905–908 Co-existent autoimmune chronic hepatitis was reported in one case.909 The autopsy of a 59-year-old female with Gaucher disease type I who died following sepsis, disseminated intravascular coagulation, and multiorgan failure, 5 years after being started on ERT, demonstrated a paucity of Gaucher cells in spleen and liver, the latter containing a multinodular cholangiocarcinoma.910

The ultrastructural aspects of the Gaucher cell have been described in detail.5,903,905,911 The cytoplasm is filled with spindle or rod-shaped inclusion bodies bounded by a limiting membrane; they measure 0.6 µm in diameter (Fig. 4.67). In cross section the inclusions contain numerous small tubules, 13–75 nm in diameter. Acid phosphatase activity has been localized to the inclusions by electron microscopic histochemistry.911 Freeze-fracture and X-ray diffraction analysis of the purified deposits have shown them to consist of twisted membranous bilayers 6 µm in thickness.912 The iron in the Gaucher cell is dispersed as individual micelles of ferritin.913

Definition and History

In 1894, Otto Binswanger reported eight patients with slowly progressive mental deterioration and pronounced white matter changes on a macroscopic examination of the brain performed in one of them. In a communication to the German psychiatrists in Munich, Alzheimer subsequently reported the microscopic features, including severe gliosis of the white matter and hyalination, intimal fibrosis, and onion-skinning of the long medullary arteries, and firstly used the terms ‘Binswanger form’ or ‘encephalitis subcorticalis chronica Binswanger's.’

Subsequently, several other synonyms, such as ‘subcortical arteriosclerotic encephalopathy of Binswanger's type’ or ‘chronic microvascular leukoencephalopathy’ were proposed. Today, Binswanger disease (BD) is considered as a form of vascular dementia characterized by diffused white matter lesions and a varying degree of lacunar infarction in the basal ganglia and white matter. However, more than one century after its initial description, intense controversy still surrounds the clinical manifestations, pathophysiology, and prevalence of BD.

2 Copper and Other Phenotypes

Recent results support the notion that metal-related abnormalities accompany cognitive deterioration, as suggested by the correlation between an increase in serum copper not bound to ceruloplasmin (“free” copper) and worsening on the Mini–Mental Status Examination.82

Copper, manganese, and selenium are required in small amounts as components of antioxidant enzymes; they are actively involved in protecting the body against oxidative stress.83 Therefore, determining their plasma levels may contribute to improved assessment of the health and nutritional status of certain populations.

The mean plasma levels of copper, manganese, and selenium among the healthy adult population living in Andalusia were found to be similar to those measured among comparable populations in earlier studies and within the range of normality.44 With greater age, the mean plasma values of copper tended to rise. In general, the anthropometric parameters measured did not significantly modify the plasma levels of the elements studied, except that there was a slight tendency for copper levels to decrease with rising BMI. Thus, the sedentary population presented plasma levels of copper that were slightly higher than those of the more active population.

Various factors have been proposed as possibly affecting plasma levels of copper, including age. It has been shown that there is a negative correlation between age and copper levels in both men and women.43 Although copper deficiency is not common among humans, in a recent study, 4.4% (15 persons) of the total population (340 persons) had hypocupremia (plasma concentrations < 75 μg/dL).44 This might be explained by the low copper content in the geographic area of Andalusia.84 Among the study population, there was a tendency for obese persons to present lower plasma levels of copper. This could be related to the fact that, in this particularly obese population, there was a lower consumption of polyunsaturated fats.85 Gender also influences plasma copper. Women presented significantly higher mean plasma copper levels compared to men in a study by Johnson.86 This finding could be due to the fact that adult women (aged 20–59 years) demonstrate higher levels of absorption and thus a more rapid turnover of copper.86 Furthermore, it has been reported that smoking increases plasma levels of copper and that these levels are positively correlated with CuZn–SOD activity. Both plasma copper and CuZn–SOD activities have been shown to increase in response to the chronic inflammation of the respiratory tract found in smokers.83

It was recently demonstrated that the zinc-finger domain of transcription factor Sp1 functions as a sensor of copper which regulates copper transporter 1 up and down in response to copper concentration variations.87

Neurodegenerative Diseases with Dementia

Dementia is usually a chronic syndrome characterized by various symptoms of cognitive deterioration, especially memory, but also a decline in other cognitive abilities (International Classification of Diseases, 10th revision—ICD-10). The global prevalence of dementia is about 24 million [91]. According to the Diagnostic and Statistical Manual of Mental Disorders, 5th revision (DSM-V) the term “dementia” has been replaced by major or minor neurocognitive disorder. Genetic factors are important in all forms of dementia but especially in early-onset dementia [92].

Alzheimer disease (AD) is the most common cause of dementia. The neuropathological findings are neuronal and synaptic loss with amyloid-β peptide plaques and neurofibrillary tangles formed by abnormally hyperphosphorylatedmicrotubule-associated protein tau. Disease is caused by the combination of genetic and environmental factors. There are two forms of the disease. The early-onset AD (1–5% of all cases) that affects people before 65 years is usually characterized by Mendelian inheritance [93]. The autosomal dominant highly penetrant genetic pattern of inheritance is observed in families with early-onset disease caused by mutations in three genes, APP, PSEN1, and PSEN2[92].

Late-onset AD, after 65 years of age, is more common than the early one; it has no consistent mode of transmission and the genes involved increase disease risk in a non-Mendelian fashion [91,93]. The major late-onset Alzheimer susceptibility gene is APOE ε4—encoding apolipoprotein E. The most common genotype is APOE ε3ε3. The APOE ε4 allele increases the risk of AD by two or three times [91]. The risk of AD for APOE ε4ε4 carriers at the age of 60–69 years is much higher than for APOE ε3ε3 carriers [94].

GWAS have led to the identification of other genes linked to the risk of late-onset AD, including BIN1, CLU, PICALM, CR1, CD2AP, CD33, EPHA1, ATXN1, ABCA7, the MS4A4A/MS4A4E/MS4A6E cluster, and EPHA1[91,93]. Variants in these genes are linked to significant differences in risk of AD, but their effects are much smaller than that of APOE. NGS enabled detection of a rare variant of TREM2 carrying risk comparable with that of APOE ε3ε4. Two WES studies identified mutations in NOTCH3 and in SORL1, the latter in the group of patients with early-onset AD [94]. The Alzheimer’s Disease Sequencing Project is currently under way. Using WGS, 582 subjects from 111 families will be examined with the aim to identify new genomic variants contributing to increased disease risk as well as a protective constellation of genes (https://www.niagads.org/adsp/content/home). Moreover, several research teams have joined the International Genomics of Alzheimer’s Project with the goal of carrying out the largest genetics study of AD to date and providing further insights into the inheritance of the condition (www.alz.org).

Frontotemporal dementia (FTD), in its familial (approximately 50% of cases) and sporadic forms, is characterized by gradual damage of neurons in the frontal and temporal lobes with slowly progressive dementia and behavioral changes and, at later stage, by psychomotor slowing and apathy. The two causal genes MAPT and PGRN account for 10–20% of familial FTD. Mutations in TDP43, FUS, UBQLN2, VCP, and CHMP2B are associated with some familial FTD cases. Most recently, a large intronic hexanucleotide (GGGGCC) expansion in the C9orf72 gene was associated with 5% of cases of familial as well as some sporadic forms of FTD. The hexanucleotide GGGGCC expansion ranges from zero to around 30 copies in unaffected individuals to several thousand repeats in mutation carriers. The detection of such a repeat expansion by current NGS technologies is not possible [95,96].

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease in which upper and lower motor neurons are lost, accounting for respiratory muscle paralysis within 3–5 years after the disease onset. ALS has familial (10%) and sporadic (90%) forms. Missense mutations in the gene encoding the antioxidant enzyme Cu/Zn superoxide dismutase, SOD1, together with mutations in C9orf72, TDP43, and FUS, account for approximately 65% of the familial ALS cases [95,96]. Other rare genes linked to familial ALS include MAPT, PGRN, VCP, UBQLN2, and CHMP2B. Furthermore, it has been established that symptoms of FTD and ALS can co-occur in the same patient. Interestingly, the most convincing direct molecular link between ALS and FTD has been the identification of a hexanucleotide GGGGCC expansion in C9orf72 in families with ALS, FTD, and overlapping ALS–FTD syndrome. This expansion accounts for approximately 40% of familial ALS, 10% of sporadic ALS, 5% of sporadic FTD, and up to 80% of familial ALS–FTD cases; hence, it makes GGGGCC repeat expansion the most common cause of ALS and FTD. Accordingly ALS and FTD are supposed to be linked genetically and have overlapping phenotypes, and each disease should now be recognized as representative of a continuum of a broad neurodegenerative disorder, supporting the hypothesis about a spectrum of neurodegenerative diseases, further confirmed by the coexistence of various neurodegenerative diseases in relatives of patients with ALS [95,96].

Huntington disease (HD) is a rare progressive autosomal dominant neurodegenerative condition associated with the accumulation of intracellular pathogenic proteins. The course of the disease is variable, and dementia can occur at any stage. HD is caused by a mutation in the HTT gene. The diagnosis of HD is based on the estimation of the CAG repeat length at the HTT locus. The number of trinucleotide CAG repeats in the normal HTT gene is reported to be less than 27. Individuals affected with HD typically have at least one HTT allele containing a CAG repeat size of 40 or greater. Currently such analysis cannot be performed using standard NGS technology.